WO2012116370A1 - Procédés et systèmes utilisant des profils pharmacocinétiques et pharmacodynamiques dans régimes thérapeutiques d'interféron-alpha - Google Patents

Procédés et systèmes utilisant des profils pharmacocinétiques et pharmacodynamiques dans régimes thérapeutiques d'interféron-alpha Download PDF

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WO2012116370A1
WO2012116370A1 PCT/US2012/026792 US2012026792W WO2012116370A1 WO 2012116370 A1 WO2012116370 A1 WO 2012116370A1 US 2012026792 W US2012026792 W US 2012026792W WO 2012116370 A1 WO2012116370 A1 WO 2012116370A1
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interferon
patient
concentrations
therapeutic regimen
ifn
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PCT/US2012/026792
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English (en)
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Eric A. Grovender
William P. Van Antwerp
Jeffrey Lande
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Medtronic, Inc.
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Priority to CN2012800004213A priority Critical patent/CN102985104A/zh
Publication of WO2012116370A1 publication Critical patent/WO2012116370A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142—Pressure infusion, e.g. using pumps
    • A61M5/14244—Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/168—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body
    • A61M5/172—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic
    • A61M5/1723—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic using feedback of body parameters, e.g. blood-sugar, pressure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142—Pressure infusion, e.g. using pumps
    • A61M2005/14208—Pressure infusion, e.g. using pumps with a programmable infusion control system, characterised by the infusion program

Definitions

  • This invention is in the field of therapeutic agents and their pharmacokinetics and pharmacodynamics.
  • Hepatitis B virus (HBV) infection is a major public health challenge, with an estimated 730,000 chronically infected adults in the United States alone.
  • Hepatitis C virus (HCV) is an even more deadly type of hepatitis virus which is associated with chronic liver diseases such as liver cirrhosis and cancer.
  • IFN-oc Human recombinant interferon-alpha
  • IFN-oc Human recombinant interferon-alpha
  • IFN-oc Human recombinant interferon-alpha
  • IFN-oc is approved in many countries for the treatment of hepatitis B and C infection, either as a monotherapy or in combination with additional agents such as small molecule nucleoside analogs.
  • IFN-oc is also approved in many countries for treating patients with cancer.
  • IFN-oc generally stimulates patients' immune systems and is, for example, one of the earliest cytokines released by antigen presenting cells as part of the innate immune response. IFN-oc modulates NK and T cell responsiveness, which consequentiy drives the immune response in patients.
  • IFN-oc exhibits a number of virus specific effects and,, for example, is observed to down-regulate hepatitis B virus gene expression in vivo by tumor necrosis factor-dependent and independent pathways (Guidotti et al., J Virol. 1994 Mar;68(3):1265-70).
  • IFN-oc pressure on viral infections may be clinically important and increasing the dose level of interferon appears to improves the success rate of viral therapy, as measured by sustained viral response, "SVR", (see, e.g., Shudo et al., J Viral Hepat 2008a;15(5):379-82).
  • SVR sustained viral response
  • Pegylated IFN-oc2b (PEGIntron®) is approved for the treatment of hepatitis C. Its half-life is about 40 hours and it is administered once weekly by SC injection.
  • PEGIntron® being a modified IFN-oc2b molecule, compared to unpegylated IFN-oc 2b, it has reduced affinity for the IFN-oc 2b receptor, distributes differently in the body and hence its safety and efficacy are not necessarily comparable to IFN-oc2b.
  • Interferon therapies further carry a risk of side effects, including neutropenia, thrombocytopenia, serious depression, and systemic flu-like symptoms. Interferon therapies can also exacerbate or induce fatigue in patients with chronic viral infection and compromise quality of life. Clinical evidence suggests that the incidence and/ or severity of certain AEs (adverse events) associated with conventional interferon therapies correlate with peak blood levels or with rapidly changing blood levels of interferon (see, e.g., Arimura et al., J Neurovirol 2007;13(4):364-72, Bonnem et al., J Biol Response Mod 1984;3(6):580-98 and Budd et al., Cancer Chemother Pharmacol 1984;12(l):39-42).
  • Near-constant blood levels combined with the maximal levels of penetration into non-hepatic and hepatic tissues achieved by nonpegylated interferons may be able to decrease the incidence and/or severity of certain AEs as well as improve therapeutic efficacy by exposing HBV and HCV to an environment that comprises continuous, physiologically effective interferon-a levels in as many tissues as possible.
  • the continuous subcutaneous administration of a nonpegylated, fully biopotent interferon-a (e.g. INTRON A®) via an external pump infusion system (e.g. the Medtronic MiniMed Paradigm® Insulin Infusion System) results in more constant blood interferon- ⁇ levels.
  • relatively stable blood interferon- ⁇ levels appear to allow patients to tolerate relatively high doses of interferon that can provide improved therapeutic efficacy (e.g. SVR rates).
  • methods and systems that facilitate the optimized doses of interferon- ⁇ are desirable.
  • pharmacokinetic and/or pharmacodynamic markers can be utilized in order to, for example, optimize therapeutic regimens for patients treated with IFN-a.
  • results from pharmacokinetic and pharmacodynamic analyses of clinical trial data demonstrate that pharmacokinetic profiles of interferon-a administered to patients via a continuous administration regimen can be correlated with aspects of disease states and consequently be used to optimize patient treatment.
  • Embodiments of the invention disclosed herein address important needs in this technology and, for example, allow medical personnel to administer optimized interferon- ⁇ dosing regimens, including those designed to address the unique parameters of an individual patient's physiology.
  • One illustrative embodiment of the invention is a method of characterizing one or more pharmacokinetic profile(s) resulting from a therapeutic regimen that comprises administering interferon-a to a patient via a continuous infusion device.
  • the one or more pharmacokinetic profile(s) are correlated with a viral response to the therapeutic regimen (e.g. an early virological response (EVR), and/or a sustained virological response (SVR); and/or viral clearance).
  • EMR early virological response
  • SVR sustained virological response
  • Such methods comprise the steps of obtaining one or more interferon-a serum concentration measurements from the patient following initiation of the therapeutic regimen. These measurements can then be used to determine one or more pharmacokinetic factors such as a percent fluctuation (PF%) of interferon- ⁇ concentrations in the patient, a standard deviation of interferon- ⁇ concentrations in the patient, and a coefficient of variation of interferon- ⁇ concentrations in the patient, and in this way characterize a pharmacokinetic profile of interferon in a patient specific manner.
  • PF% percent fluctuation
  • the methods include determining if the pharmacokinetic profile of interferon- ⁇ conforms to one or more parameters (e.g. exhibits relatively uniform concentration levels in vivo) that identifies the patient as more likely to exhibit a viral response as compared to patients having pharmacokinetic profiles that do not conform to the parameter (s).
  • artisans can then select one or more continued therapeutic regimen(s) or course(s) of action based upon the determination(s).
  • the continued therapeutic regimen or course of action can comprise maintaining the therapeutic regimen for a duration of at least 4, 5, 6, 7, 8, 12, 24, 36 or 48 weeks.
  • the course of action can also or alternatively comprise initiating a modified therapeutic regimen for the patient that comprises an increased dose of interferon- ⁇ (e.g.
  • the course of action can comprise discontinuing the therapeutic regimen.
  • Yet another embodiment of the invention is a system for administering interferon- ⁇ to a patient.
  • the system comprises a continuous infusion pump having a medication reservoir comprising interferon- ⁇ , and a processor operably connected to the continuous infusion pump and comprising a set of instructions that causes the continuous infusion pump to administer the interferon-a to the patient according to a patient-specific therapeutic regimen.
  • this patient- specific therapeutic regimen is made by administering interferon- ⁇ to the patient via a continuous infusion pump according to a test therapeutic regimen and then observing concentrations of interferon- ⁇ present in the serum of the patient that result from the test therapeutic regimen so as to obtain information on whether a pharmacokinetic profile of the interferon- ⁇ conforms to one or more parameters that identify the patient as more likely to exhibit a viral response to interferon- ⁇ as compared to patients having pharmacokinetic profiles that do not conform to the parameter (s).
  • the processor in this system uses instructions that result from the observed profile(s) and comprises an increased dose of interferon- ⁇ ; or a decreased dose of interferon- ⁇ as compared to the test therapeutic regimen.
  • interferon- ⁇ in the manufacture of a composition adapted for a continuous infusion apparatus.
  • the interferon- ⁇ composition is manufactured so that a continuous infusion apparatus using the composition modulates one or more pharmacokinetic proffle(s) of the manufactured composition.
  • the composition is manufactured so that, when delivered via a continuous infusion device, the percent fluctuation (PF%) of interferon- ⁇ concentrations in vivo are not greater than a predetermined value, for example not greater than about 100, 150 or 200%.
  • the composition is manufactured to maintain mean circulating levels of interferon- ⁇ in serum of a patient above a specific steady state concentration, for example one that ranges from 30-35 IU/mL (e.g. is at least 33 IU/mL).
  • a related embodiment of the invention is the use of interferon- ⁇ in the manufacture of a composition for treating hepatitis C infection for use in a continuous infusion apparatus, wherein the interferon- ⁇ composition is manufactured to allow the continuous infusion apparatus to maintain mean circulating levels of interferon- ⁇ in serum of a patient above a steady state concentration that ranges from 30-35 IU/ mL (e.g. is at least 33 IU/mL) for at least 1 to at least 48 weeks when administered subcutaneously.
  • Another related embodiment of the invention is a method of administrating a therapeutic regimen comprising interferon-a delivered to a patient infected with a hepatitis C virus via a continuous infusion device, the method comprising determining average serum interferon- ⁇ concentrations in the patient that are occurring on about a third day of administering interferon- ⁇ , wherein serum interferon-a concentrations of above about 30-35 IU/mL identify the patient as having a greater probability of achieving rapid virologic response (RVR) as compared to a patient having serum interferon- ⁇ concentrations below about 30-35 IU/mL.
  • RVR rapid virologic response
  • these observed serum interferon- ⁇ concentrations can further be used to design a modified therapeutic regimen for the patient that comprises an increased dose of interferon- ⁇ ; or alternatively, a decreased dose of interferon-a.
  • Figure 1 illustrates median serum IFN concentrations vs. nominal study time. IFN concentrations missing for any reason were not included in the determination of the median value. Detailed summary statistics of the serum IFN concentrations are provided in Figure 7. For the PEG-IFN arm after Day 3, the serum IFN concentrations represent an upper bound for the weekly C mn .
  • FIG. 2 illustrates selected IFN exposure variables through 4 and 12 weeks for the Continuous Subcutaneous IFN Delivery (CSID) arms of the COPE-HCV clinical trial. Boxes range the 25th and 75th percentile with horizontal line at the median and solid diamonds at the mean. Whiskers range the 10th and 90th percentiles. Empty circles represent outliers. Detailed summary statistics for the complete set IFN exposure variables are provided in Figures 8 and 9.
  • Figure 3 illustrates stability in serum IFN concentrations resulting from CSID vs. historical controls from Day 3 through 4 (left) and 12 (right) weeks of therapy. Boxes range the 25th and 75th percentile with horizontal line at the median and solid diamonds at the mean. Whiskers range the 10th and 90th percentiles.
  • the PF% of the PEG arm for COPE-HCV was not calculated for comparison with the CSID arms due to the infrequent sampling relative to once-weekly dosing for PEG-IFN.
  • PF% was estimated using published PK model parameters for individual subjects (see, e.g. Dahari H, et al.
  • Figure 5 illustrates subject disposition through the week 12 efficacy decision. Subjects were required to have a ⁇ 2-loglO decline in their plasma HCV RNA after 12 weeks in order to continue drug therapy.
  • Figure 6 illustrates subject disposition and early virologic response (EVR) after 12 weeks of therapy.
  • Figure 7 illustrates serum IFN concentration detailed summary statistics.
  • the column headings provide the number of mITT subjects by arm (N). The number of IFN concentration measurements that are available for each study visit are also denoted (n).
  • Figure 8A-B illustrates IFN exposure variables, depicting week 4 interferon exposure variable descriptive statistics.
  • AUC summary statistics are reported to 3 significant digits. All other Interferon Exposure Variable Descriptive Statistics are reported to 1 decimal place.
  • AUC, C avg and C max are based on the nominal time interval from Baseline through Week 4. In contrast, PF% and C mn are based on the nominal time interval from Day 3 through Week 4.
  • Figure 9A-B illustrates week 12 interferon exposure variable descriptive statistics.
  • (#)AUC summary statistics are reported to 3 significant digits. All other Interferon Exposure Variable Descriptive Statistics are reported to 1 decimal place.
  • AUC, C avg and C max are based on the nominal time interval from Baseline through Week 12. In contrast, PF% and C mm are based on the nominal time interval from Day 3 through Week 12.
  • Figure 10 illustrates detailed results from a power model analysis, depicting week 4 IFN exposure variable power model analysis results. None of the interferon exposure variables had a statistically significant (p ⁇ 0.05) quadratic term.
  • Figure 11 illustrates week 4 IFN exposure variable power model analysis results.
  • Figure 12 illustrates week 12 IFN exposure variable power model analysis results. None of the interferon exposure variables had a statistically significant (p ⁇ 0.05) quadratic term.
  • Figure 13 illustrates week 12 IFN exposure variable power model analysis results.
  • Figure 14 illustrates an analysis of PD relationships, depicting multivariate regression for week 4 C mn as a predictor of RVR and discontinuation.
  • A Independent variables used in the multivariate regression analysis. Multivariate logistic regression models were used to assess the ability of the Week 4 IFN exposure variables to predict RVR and discontinuation before Week 12 of therapy. The independent variables listed here were provided to the backward selection algorithm.
  • B Multivariate Regression Results: Week 4 Exposure Variables & Baseline Characteristics as Predictors of RVR. Variables with p-values > 0.05 were excluded from the final form of the model by the backward selection algorithm.
  • C Multivariate Regression Results: Week 4 Exposure Variables & Baseline Characteristics as Predictors of Discontinuation before Week 12.
  • Figure 15 illustrates Receiver Operating Characteristic curves for week 4 C mm as a predictor of RVR and discontinuation, depicting a Receiver Operating Characteristic curve for week 4 IFN C mm as a predictor for RVR.
  • Figure 16 illustrates a Receiver Operating Characteristic curve for week 4 IFN C mm as a predictor for discontinuation before week 12. Only discontinuations for reasons other than the Week 12 futility rule are included ( ⁇ 2-logl0 drop HCV RNA).
  • Figure 17 illustrates a multivariate contingency table for week 4 C mm as a predictor for RVR and therapy discontinuation.
  • the 78 CSID subjects in the mIT population 60 met the prospective exclusion rules for Week 4 C mn .
  • Figure 18 illustrates Day 3 IFN concentration as a predictor of RVR.
  • A Independent variables used in the multivariate regression analysis. Multivariate logistic regression models were used to assess the ability of a single IFN concentration measurement from the Day 3 study visit to predict RVR. The independent variables listed here were provided to the backward selection algorithm. For the Day 3 study visit, the actual time on CSID had a median of 2.1 days and range of 1.6-5.2 days.
  • B Multivariate Regression Results: Day 3 Serum IFN Concentration & Baseline Characteristics as Predictors of RVR.
  • Figure 19 illustrates a contingency table for Day 3 IFN concentration as a univariate predictor for RVR and therapy discontinuation.
  • Figure 20 illustrates a Receiver Operating Characteristic curve for Day 3 IFN concentration as a predictor for RVR.
  • Figure 21 illustrates a correlation of Week 4 viral decay with Week 4 IFN exposure variables.
  • the correlation of Week 4 viral decay with C avg , PF%, C ma prison and C mn was assessed by reporting and testing whether parametric (Pearson's coefficient) and non-parametric (Spearman's ⁇ and/or Kendall's ⁇ ) measures of correlation are significantly different from 0, as presented in Figure 21 and illustrated by Figure 22.
  • Figure 22 illustrates scatterplots of Week 4 viral decay vs. Week 4 IFN exposure variables.
  • Figure 23 illustrates RVR and viral kinetics in subjects with refractory host or virus genotypes.
  • RVR by treatment arm and host IL28B genotype. Column headings provide the number of mITT subjects by arm. IL28B genotype information is available for 68 / 106 mITT subjects, as this was added to the protocol after the study was initiated.
  • Figure 24A shows the stability of serum IFN levels from continuous IFN therapy (PF% from Day 3 through Week 4) compared to historical controls. Percent fluctuation for IFN and PEG-IFN calculated from data published for week 4 of therapy (see, e.g. GLUE et al., Clin Pharmacol Ther 2000;68(5):556-67). Dosing regimens for IFN (INTRON A) and PEG-IFN (PEGINTRON) are taken from the respective package inserts.
  • Figure 24B shows a detailed relationship of significant predictors of RVR or discontinuation from multivariate logistic regression analyses.
  • the two significant continuous variables (baseline HCV RNA and MWl-IFN concentration) are plotted against each other for each combination of the two significant categorical variables - IL28B genotype and gender.
  • the critical value found for the achievement of RVR is 32.8. Genotypes are grouped into CC, CT, TT or unknown, which are indicated by "NA” in the figure.
  • Figure 25 illustrates Neopterin PD response.
  • A Time-averaged Neopterin response from individual baseline (Eavg). Eavg is based on the nominal time interval from Baseline through Week 4 or Week 12.
  • B Time-averaged Neopterin response from individual baseline (Eavg).
  • Figure 26 illustrates (A) correlation of Neopterin response with IFN exposure. CSID arms only.
  • B Scatterplots of Neopterin Eavg vs. IFN C avg .
  • Figure 27 illustrates (A) correlation of Neopterin response with viral decay. PEG and CSID subjects. (B) Scatterplots of Viral Decay vs. Neopterin Eavg. PEG and CSID subjects.
  • Figure 28A presents an exemplary generalized computer system 202 that can be used to implement elements of the present invention.
  • Figure 28B presents one embodiment of a specific illustrative computer system embodiment that can be used with embodiments of the invention in the treatment of Hepatitis virus infection.
  • pharmacokinetics is used according to its art accepted meaning and refers to the study of the action of drugs in the body, for example the effect and duration of drug action, the rate at they are absorbed, distributed, metabolized, and eliminated by the body etc. (e.g. the study of a concentration of interferon-a in the serum of the patient following its administration via a specific dose or therapeutic regimen).
  • pharmacodynamics is used according to its art accepted meaning and refers to the study of the biochemical and physiological effects of drugs on the body or on microorganisms such as viruses within or on the body, the mechanisms of drug action and the relationship between drug concentration and effect etc. (e.g. the study of hepatitis virus present in a patient's plasma following one or more therapeutic regimens).
  • pharmacodynamic models and “pharmacodynamic parameters” as used herein include interferon and/ or viral kinetic models and interferon and/ or viral kinetic parameters (e.g. in vivo concentration).
  • Various models to estimate parameters associates with Hepatitis B and C infections have been developed, and may be adapted for use with methods described herein.
  • viral kinetic models include, but are not limited to, models disclosed in the following references: the contents of which are incorporated by reference: Perelson, et al. (2005), Hepatology 42(4): 749-754; Talal, et al. (2006), Hepatology 43(5): 943-953; Dahari et al. (2007), J Theor Biol 247(2): 371-81; Dahari et al.
  • continuous administration e.g. as in a “continuous administration regimen”
  • continuous infusion e.g. as in a “continuous infusion regimen”
  • continuous infusion regimen exclude administration or infusion of an agent via a bolus, and mean delivery of an agent such as interferon-a in a manner that, for example, avoids significant fluctuations in the in vivo concentrations of the agent throughout the course of a treatment period (e.g. as occur when administering an agent such as interferon-a via one or more boluses spaced over a periods of time such as 12 hours, 1 or 2 or more days).
  • interferon- ⁇ typically with a continuous infusion pump device
  • continuous interferon- ⁇ may be administered according to art accepted methods, for example via subcutaneous, interperotineal, or intravenous injection at appropriate intervals, e.g. at least hourly, for an appropriate period of time in an amount which will facilitate or promote in vivo inactivation of hepatitis B or C viruses.
  • continuous infusion system refers to a device for continuously administering a fluid to a patient parenterally for an extended period of time or for intermittently administering a fluid to a patient parenterally over an extended period of time without having to establish a new site of administration each time the fluid is administered.
  • the fluid typically contains a therapeutic agent or agents.
  • the device typically has one or more reservoir(s) for storing the fluid(s) before it is infused, a pump, a catheter, cannula, or other tubing for connecting the reservoir to the administration site via the pump, and control elements to regulate the pump.
  • the device may be constructed for implantation, usually subcutaneously. In such a case, the reservoir will usually be adapted for percutaneous refilling.
  • An exemplary "continuous infusion system” is the Medtronic MiniMed Paradigm® Insulin Infusion System.
  • administer means to introduce a therapeutic agent into the body of a patient in need thereof to treat a disease or condition.
  • treating and/or “treatment” refers to the management and care of a patient having a pathology such as a viral infection or other condition for which administration of one or more therapeutic compounds is indicated for the purpose of combating or alleviating symptoms and complications of those conditions. Treating includes administering one or more formulations of the present invention to prevent the onset of the symptoms or complications, alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
  • treatment or “therapy” refer to both therapeutic treatment and prophylactic or preventative measures.
  • treating does not require complete alleviation of signs or symptoms, does not require a cure, and specifically includes protocols which have only a marginal effect on the patient.
  • terapéuticaally effective amount refers to an amount of an agent (e.g. a cytokine such as interferon-a) effective to treat at least one sign or symptom of a disease or disorder in a human.
  • Amounts of an agent for administration may vary based upon the desired activity, the diseased state of the patient being treated, the dosage form, method of administration, patient factors such as the patient's sex, genotype, weight and age, the underlying causes of the condition or disease to be treated (e.g. infection with a specific virus, viral genotype etc.), the route of administration and bioavailability, the persistence of the administered agent in the body, the formulation, and the potency of the agent. It is recognized that a therapeutically effective amount is provided in a broad range of concentrations. Such range can be determined based on in vitro and/ or in vivo assays.
  • therapeutic regimen refers to, for example, a part of treatment plan for an individual suffering from a pathological condition (e.g. chronic hepatitis infection) that specifies factors such as the agent or agents to be administered to the patient, the doses of such agent(s), the schedule and duration of the treatment etc.
  • pathological condition e.g. chronic hepatitis infection
  • Therapeutic regimens include, for example, the continuous administration of interferon-a according to embodiments of the invention.
  • profile is used according to its art accepted meaning and refers to the collection of results of one or more analyses or examinations of: (1) the presence of; or (2) extent to which an observed phenomenon exhibits various characteristics.
  • Illustrative profiles typically include the results from a series of observations which, in combination, offer information on factors such as, for example, the presence and/or levels and/or characteristics of one or more agents infecting a patient (e.g. the hepatitis B or C virus), as well as the pharmacokinetic and/ or pharmacodynamic characteristics of one or more therapeutic agents administered to a patient as part of a treatment regimen (e.g. interferon-a), as well as the physiological status or functional capacity of one or more organs or organ systems in a patient (e.g. the liver), as well as the genotype of one or more single nucleotide polymorphisms in a patient etc.
  • agents infecting a patient e.g. the hepatitis B or C virus
  • Hepatitis B virus is a DNA virus that exists in at least eight genetically distinct genotypes. These genotypes are designated A through H and are further grouped into a number of subtypes that exhibit differing responses to therapeutic regimens.
  • Hepatitis C virus is a positively stranded RNA virus that exists in at least six genetically distinct genotypes that also exhibit differing responses to therapeutic regimens. These genotypes are designated Type 1, 2, 3, 4, 5 and 6, and their full length genomes have been reported (see, e.g.
  • Type la M62321, AF009606, AF011753, Type lb: AF054250, D13558, L38318, U45476, D85516; Type 2b: D10988; Type 2c: D50409; Type 3a: AF046866; Type 3b: D49374; Type 4: WC-G6, WC-G11, WG29 (Li-Zhe Xu et al, J. Gen. Virol. 1994, 75: 2393-98), EG-21, EG-29, EG-33 (Simmonds et al, J. Gen. Virol. 1994, 74: 661-668), the contents of which are incorporated by reference.
  • Interferon-alpha Human recombinant interferon-alpha (IFN-oc) is approved in many countries for the treatment of hepatitis B and C infection.
  • PEG-IFNa is known to facilitate HBsAg clearance or seroconversion in HBV infected patients.
  • studies have shown that PEG-IFNa-based therapy is more effective than LAM monotherapy in achieving HBsAg clearance or seroconversion for both HBeAg-positive and HBeAg-negative CHB patients (Li et al., BMC Infect Dis. 2011 Jun 9;11:165. doi: 10.1186/1471-2334-11-165.
  • interferon-a As is known in the art, individual patients do not have identical physiological characteristics, and for example, commonly exhibit differing responses to the same therapeutic agent (e.g. interferon-a). Such differing physiological characteristics include therapeutic agent efficacy, tolerance as well as the clearance rate at which a therapeutic agent is removed from the body. Consequently, the optimal dosing of a therapeutic agent can be very difficult to predict, particularly in situations where high levels of the drug are concurrently associated with high efficacy as well as unpleasant side effects (e.g. interferon-a). As disclosed herein, if the dosing of interferon-a (e.g. non-pegylated interferon) is modulated in a manner that results in both stable as well as sustained levels of this cytokine in the patient (e.g.
  • interferon-a e.g. non-pegylated interferon
  • this therapeutic agent can play an enhanced role preventing immune exhaustion and enhancing the adaptive immune response that is directed towards the hepatitis B and C viruses, thereby leading to greater rates of desirable phenomena such as clearance and/ or seroconversion.
  • aspects of the invention disclosed herein relate to and are part of a clinical trial designed to compare the safety and efficacy of the continuous infusion of interferon with the current standard of care for chronic hepatitis C infection.
  • This study is termed the "COPE-HCV" clinical trial, see, e.g. CUnicalTrials.gov: Identifier: NCT00919633.
  • This study includes patients who are diagnosed with chronic hepatitis C genotype 1 infection and who have received no previous interferon or other anti-HCV treatment.
  • the safety objective in this study is to determine the tolerability and safety of continuous interferon infusion versus the standard of care, at the standard-of-care dose regimen when given with oral weight-based ribavirin.
  • the efficacy objective in this study is to determine the virologic response to continuous interferon infusion in subjects with hepatitis C genotype 1 infection, and to test a selected continuous interferon dose against standard treatment.
  • All subjects will also receive oral ribavirin (1000 mg/day if weight ⁇ 75 kg; 1200 mg/day if weight >75 kg).
  • Intron A® interferon alfa- 2b, recombinant
  • Peglntron® peginterferon alfa-2b
  • the interferon-a is continuously administered via the MiniMed Paradigm® Insulin Infusion System, Medtronic, Inc.
  • the viral response is the response of a hepatitis B or hepatitis C virus that infects the patient to a specific therapeutic regimen and comprises an early virological response (EVR) and/or a sustained virological response (SVR).
  • EMR early virological response
  • SVR sustained virological response
  • the viral response comprises a 1, 2 or 3 log drop in viral particles observed in serum of the patient, typically within a certain time period following initiation of the therapeutic regimen, for example within 1, 2, 3 or 4 weeks.
  • the viral response comprises viral clearance at the end of the therapeutic regimen.
  • viral clearance means undetectable HCV RNA in persons infected with HCV.
  • viral clearance means undetectable non-integrated HBV DNA (e.g. undetectable HBV virion DNA circulating in the blood) in persons infected with HBV.
  • viral load can be measured by a variety of procedures known in the art, for example, by measuring the titer or level of virus in serum. These methods include, but are not limited to, a quantitative polymerase chain reaction (PCR) and/or a branched DNA (bDNA) test. Many such assays are available commercially, including a quantitative reverse transcription PCR (RT-PCR). While viral titers are the most important indicators of effectiveness of a dosing regimen, other parameters can also be measured as secondary indications of effectiveness. Secondary parameters include reduction of liver fibrosis; and reduction in serum levels of particular proteins.
  • PCR polymerase chain reaction
  • bDNA branched DNA
  • RT-PCR quantitative reverse transcription PCR
  • HBsAg clearance and seroconversion characterized by the loss of serum HBsAg with or without anti-HBs antibody development, are the main markers of a successful immunological response to HBV infection and the closest outcome to clinical cure.
  • HBsAg clearance is defined as the disappearance of HBsAg from the serum.
  • a decline in hepatitis B virus surface antigen (HBsAg) predicts clearance, but does not correlate with quantitative HBeAg or HBV DNA levels (Wiegand et al., Antivir Ther. 2008;13(4):547-54).
  • HBsAg seroconversion is defined as HBsAg disappearance and anti- HBs antibody appearance.
  • HCV RNA levels were used to calculate the viral decay as function of time for all COPE-HCV study subjects.
  • V t is the viral load (IU HCV / mL) at time /
  • V 0 is the viral load (IU HCV / mL) at pre- dose Baseline
  • VD t is the viral decay (dimensionless).
  • Embodiment of the invention include methods of characterizing a pharmacokinetic profile resulting from a therapeutic regimen that comprises administering non-pegylated interferon-a to a patient via a continuous infusion device.
  • the pharmacokinetic profile correlates with a viral response to the therapeutic regimen and can used to used to address and/or overcome problematical phenomena observed in therapeutic regimens that use interferon-a to fight viral infections (e.g. in patients infected with the hepatitis B or hepatitis C virus).
  • the methods of the invention comprise the steps of obtaining a plurality of interferon-a serum concentration measurements from the patient following initiation of the therapeutic regimen, obtaining at least 1, 2, 3, 4, 5, 6 or more samples from the patient over the period of time (e.g. samples taken from serum, plasma or whole blood over a period of 1, 2, 3, 4, 5, 6, or 7 days). Then, the plurality of interferon- a concentration measurements is used to observe one or more characteristics of the interferon- ⁇ concentrations in the patient that result from this therapeutic regimen so that one or more aspects of its pharmacokinetic profile can be characterized. In some embodiments of the invention, the one or more characteristics of the interferon-a concentrations that are observed include the percent fluctuation (PF%) of interferon-a concentrations in the patient.
  • PF% percent fluctuation
  • the one or more characteristics of the interferon- ⁇ concentrations that are observed include a standard deviation of interferon- ⁇ concentrations in the patient. In some embodiments of the invention, the one or more characteristics of the interferon- ⁇ concentrations that are observed include determining a coefficient of variation of interferon- ⁇ concentrations in the patient. In some embodiments of the invention, the one or more characteristics of the interferon- ⁇ concentrations that are observed include determining the Cmin of this therapeutic agent in the patient. In some embodiments of the invention, the one or more characteristics of the interferon- ⁇ concentrations that are observed include determining the Cmax of this therapeutic agent in the patient. In some embodiments of the invention, the one or more characteristics of the interferon- ⁇ concentrations that are observed include determining the Cavg of this therapeutic agent in the patient.
  • the methods of the invention further comprises determining if the pharmacokinetic profile conforms to a parameter that identifies the patient as more likely to exhibit a viral response as compared to patients having pharmacokinetic profiles that do not conform to the parameter; and then selecting a continued therapeutic regimen or course of action based upon said determination.
  • the terms "conforms to a parameter" are used according to their art accepted meaning and refer to, for example a data point that is above (or below) a boundary value or inside of a range of values.
  • the parameter comprises a maximum PF% of interferon-a concentrations not greater than about 50%, 100%, 125%, 150%, 175%, 200%; 225% or 250%.
  • the parameter can comprise a standard deviation of interferon- ⁇ concentrations not greater than 5 IU/ML, 10 IU/ML, 15 IU/ML, 20 IU/ML or 25 IU/ML. In embodiments of the invention, the parameter can also comprise a coefficient of variation of interferon- ⁇ concentrations not greater than 10%, 20 %, 30% or 40%. Cmax and Cavg parameters that are associated with viral responses are discussed in the sections below and in the Examples and in the associated Figures and Tables (see, e.g., Figures 14-17 and 21 and Table 4).
  • the continued therapeutic regimen or course of action comprises maintaining the therapeutic regimen for a duration of at least 4, 5, 6, 7, 8, 12, 24, 36 or 48 weeks.
  • the continued therapeutic regimen or course of action comprises initiating a modified therapeutic regimen for the patient that comprises an increased dose of interferon- ⁇ (e.g. so that levels of this agent are above a concentration threshold such as about 25-40 IU/mL, and typically about 30-35 IU/mL), or a decreased dose of interferon- ⁇ (e.g. so that levels of this agent are below those that produce significant side effects in that specific patient, e.g. below about 60, 70, 80 or 90 IU/mL).
  • the course of action can comprise discontinuing the therapeutic regimen (e.g. in situations where pharmacokinetic profiling data provides evidence that a patient is unlikely to benefit from a therapeutic regimen that has been initiated).
  • Embodiments of the invention involve the continuous subcutaneous administration of interferon- ⁇ in order to maintain in vivo concentrations of this therapeutic agent above a critical efficacy threshold in vivo for a sustained period of time.
  • a serum IFN concentration of approximately 33 IU/ mL from a single blood sample a few (1.6 - 5.2) days after initiating CSID is identified as an early predictor of both RVR and discontinuation before 12 weeks.
  • Illustrative embodiments of the invention involve the continuous subcutaneous administration of interferon- ⁇ in order to maintain in vivo concentrations of this therapeutic agent above a certain IU/mL, or a certain pg/mL, for example at least 100-700 pg/mL (e.g.
  • interferon- ⁇ it is understood that values such as at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675 or 700.
  • Certain embodiments of the invention further comprise using an observation of a genomic sequence in the patient for selecting a continuing or modified therapeutic regimen or course of action.
  • the patient is infected with a hepatitis B virus and the genomic sequence comprises a single nucleotide polymorphism (SNP) designated rs2856718, rs7453920, rs3077, rs9277535, rs2284553, rs9808753 or rsl7401966.
  • SNP single nucleotide polymorphism
  • the patient is infected with a hepatitis C virus and the genomic sequence comprises a single nucleotide polymorphism (SNP) designated rsl2979860, rsl2980275, rs8099917, rsl2972991, rs8109886, rs4803223, rs8103142, rs28416813, rs4803219, rs4803217, rs581930, rs8105790, rsll881222, rs7248668 or rsl2980602.
  • SNP single nucleotide polymorphism
  • Yet another embodiment of the invention is a system for administering interferon- ⁇ to a patient.
  • the system comprises a continuous infusion pump having a medication reservoir comprising interferon- ⁇ (e.g. interferon-a is not conjugated to a polyol), and a processor operably connected to the continuous infusion pump and comprising a set of instructions that causes the continuous infusion pump to administer the interferon- ⁇ to the patient according to a patient- specific therapeutic regimen.
  • this patient-specific therapeutic regimen is made by first administering interferon- ⁇ to the patient via a continuous infusion pump according to a test therapeutic regimen and then observing concentrations of interferon- ⁇ present in the serum of the patient that result from the test therapeutic regimen so as to obtain information on whether a pharmacokinetic profile of the interferon-a conforms to a parameter that identifies the patient as more likely to exhibit a viral response to interferon- ⁇ as compared to patients having pharmacokinetic profiles that do not conform to the parameter.
  • the processor in this system uses instructions that result from the observed profile and comprises an increased dose of interferon- ⁇ ; or a decreased dose of interferon- ⁇ as compared to the test therapeutic regimen.
  • the continuous infusion pump has dimensions smaller than 15 x 15 x 15 centimeters; and/or is operably coupled to an interface that facilitates the patient's movements while using the continuous infusion pump, wherein the interface comprises a clip, a strap, a clamp or tape.
  • Yet another embodiment of the invention is the use of interferon- ⁇ in the manufacture of a composition for treating hepatitis C infection for use in a continuous infusion apparatus, wherein the interferon- ⁇ composition is manufactured to allow the continuous infusion apparatus to maintain mean circulating levels of interferon- ⁇ in serum of a patient above a steady state concentration of at least about 25, 30, 35 or 40 IU/mL (e.g. about 33 IU/mL) for at least 1 to at least 48 weeks when administered subcutaneously.
  • a serum IFN concentration of approximately 33 IU/ mL from a single blood sample a few (1.6 - 5.2) days after initiating CSID is identified as an early predictor of both RVR and discontinuation before 12 weeks.
  • This disclosure provides clinicians with the ability to more effectively tailor CSID therapy for improved efficacy and tolerability.
  • Another embodiment of the invention is a method of administrating a therapeutic regimen comprising interferon- ⁇ delivered to a patient infected with a hepatitis C virus via a continuous infusion device, the method comprising determining average serum interferon- ⁇ concentrations in the patient that are occurring on about a third day of administering interferon- ⁇ (e.g. by obtaining at least 1, 2, 3, 4, 5, or 6 or more different serum samples from the patient over a period of time such as 1, 2, 3 or more days), wherein serum interferon- ⁇ concentrations of above about 30-35 IU/mL (e.g.
  • these observed serum interferon- ⁇ concentrations are then used to design a modified therapeutic regimen for the patient that comprises an increased dose of interferon- ⁇ ; or a decreased dose of interferon- ⁇ , for example, one designed to produce serum interferon-a concentrations in the patient above about 15, 20, 25, 30, 35 or 40 IU/mL and below about 50, 60, 70, 80 or 90 IU/ mL (depending upon, for example each patient's individual IFN response and/ or tolerance levels).
  • interferon- ⁇ in the manufacture of a composition adapted for a continuous infusion apparatus.
  • the interferon- ⁇ composition is manufactured so that a continuous infusion apparatus using the composition modulates a pharmacokinetic profile the manufactured composition.
  • the composition is manufactured so that the percent fluctuation (PF%) of interferon- ⁇ concentrations in vivo are not greater than 50, 100, 150, 200 or 250%.
  • the composition is manufactured to maintain mean circulating levels of interferon- ⁇ in serum of a patient above a specific steady state concentration, for example one that is at least about 25-40 IU/mL, and typically about 30-35 IU/mL (e.g. at least about 33 IU/mL).
  • the concentrations of exogenous interferon- ⁇ present in the serum of the patient that result from administering exogenous interferon-a to the patient are sampled for a specific period of time ("window") comprising at least (or alternatively not more than) 24 or 36, 48 or 72 hours or 4, 5, 6 or 7 days.
  • the concentrations of exogenous interferon- ⁇ present in the serum of the patient that result from administering exogenous interferon- ⁇ to the patient are sampled for a period of time equal to a number of biological 1 ⁇ 2 lives of the interferon- ⁇ species administered to the patient (e.g.
  • pegylated or non-pegylated interferon- ⁇ for example for a period of time equal to between 3-20 e.g. 5, 10, 15, or 20) 1 ⁇ 2 lives of the interferon- ⁇ species administered to the patient.
  • one starts a patient on an initial dose of continuous interferon- ⁇ wait for the subject to approach steady-state, and then obtain a plurality of serum interferon measurements in order to calculate the AUC or Cavg (time- averaged interferon concentration) over a specific period of time.
  • the concentrations of exogenous interferon- ⁇ in the serum of a patient that result from administering exogenous interferon- ⁇ to the patient via a continuous administration regimen are estimated by employing a compartmental pharmacokinetic model for subcutaneous interferon-a administration.
  • a compartmental pharmacokinetic model for subcutaneous interferon-a administration.
  • other models or analysis methods can be used in embodiments of the invention in order to, for example, obtain estimates on the clearance of an interferon- ⁇ species in a patient.
  • a variety of "Compartmental Models" and “non-compartmental analysis” techniques e.g.
  • non- compartmental analysis involves using the trapezoidal rule or similar numerical methods etc.
  • pharmacokinetic analysis which can be adapted for use with embodiments of the invention.
  • a number of different illustrative models that can be adapted for use with embodiments of the invention are described in PHARMACOKINETIC & PHARMACODYNAMIC DATA ANALYSIS: CONCEPTS & APPLICATIONS. 4th edition.
  • compartmental pharmacokinetic model for subcutaneous interferon-a administration includes analyses using the following equations:
  • D is the total interferon- ⁇ content at the injection site in IU
  • C is the interferon- ⁇ concentration in serum in IU/ mL
  • V d is the apparent volume of distribution of interferon- ⁇ in mL
  • j2 is the subcutaneous infusion rate of interferon- ⁇ in IU/hour
  • an CL ⁇ is the clearance in mL/hr
  • k a is the rate constant for interferon- ⁇ absorption per hour.
  • Embodiments of the invention can further use the observations of pharmacokinetic profiles of concentrations of exogenous interferon- ⁇ in the serum of a patient that result from administering exogenous interferon- ⁇ to the patient via the continuous administration regimen to design (and optionally administer) a patient- specific continuous administration regimen for the patient, for example one that is sufficient to maintain circulating levels of the interferon- ⁇ in the patient above a mean steady state concentration of at least 100, 200, 300, 400, 500, 600 or 700 pg/mL.
  • the units "pg/mL” are used as merely one example and alternatives ways to characterize these levels such as IU/ mL are considered.
  • interferon-a e.g. 2.6 x 10 8 IU/mg for INTRON® A
  • IU per volume e.g. mL
  • Embodiments of the invention include methods of using a patient- specific regimen responsiveness profile obtained from a patient infected with hepatitis B or C virus to design a patient-specific therapeutic regimen.
  • a patient-specific regimen responsiveness profile simply means an individual's unique response to a specific therapeutic regimen (e.g. a specific dose of interferon-a) and a “patient-specific therapeutic regimen” simply means a therapeutic regimen designed in accordance with a patient's unique physiological characteristics (e.g. how quickly their body is able to clear a specific dose of interferon- ⁇ ).
  • the method comprises administering at least one therapeutic agent to the patient following a first or test therapeutic regimen and then obtaining pharmacokinetic or pharmacodynamic parameters from the patient in order to observe a patient-specific response to the first therapeutic regimen.
  • pharmacokinetic or pharmacodynamic parameters observed comprise a concentration of the therapeutic agent in the blood of the patient that results from the first therapeutic regimen (and/ or how this concentration fluctuates over time).
  • practitioners can then use the pharmacokinetic or pharmacodynamic parameters observed in the patient in response to the first therapeutic regimen to obtain a patient-specific regimen responsiveness profile.
  • This patient-specific regimen responsiveness profile is based upon an HBV or HCV infected patient's individualized physiology and necessarily takes into account patient specific factors that can influence a patients' response to treatment such as the patient's genetic profile (e.g. the presence or absence of a SNP disclosed herein), the HBV or HCV genotype(s) infecting the patient, and/or a patient's weight, treatment history, health status (e.g. if they suffer from diabetes), individual rate of exogenous interferon-a clearance, and the like.
  • This patient-specific regimen responsiveness profile is then used to design a patient- specific therapeutic regimen.
  • Embodiments of the invention include the steps of observing a variety of patient-specific factors such as a patient's prior medical treatment history, a presence or degree of a side effect that results from administering exogenous interferon-a to the patient, or a polynucleotide sequence of the patient.
  • Embodiments of the invention can also include the further step of observing a type or subtype of a hepatitis virus infecting the patient.
  • Illustrative non-pegylated and pegylated interferons for use in embodiments of the invention include interferon a-2b (e.g. Intron A) (which is not pegylated) and pegylated interferon a-2b (e.g. Peglntron).
  • Embodiments of the invention can include bolus doses of a nonpegylated interferon- ⁇ such as Intron A, for example those that range from about 1-15 million IU (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 million IU).
  • Embodiments of the invention can include weight based bolus doses of a nonpegylated interferon- ⁇ such as Intron A, for example those that range from about 50,000 IU/kg - 200,000 IU/kg (e.g. 80,000 IU/kg, 120,000 IU/kg or 160,000 IU/kg).
  • Continuous SC delivery of a nonpegylated interferon- ⁇ such as Intron A can be achieved via the Medtronic MiniMed Paradigm infusion system for 24, 26, 48 60, 72 etc. weeks of HCV therapy.
  • Doses of interferon- ⁇ used in such continuous delivery schemes can be weight based, for example the continuous delivery of 80,000 IU/kg/day, 120,000 IU/kg/day, 160,000 IU/kg/day etc. of Intron A.
  • patients can receive a defined amount, for example 3, 6, 9, or 12 million IU/day.
  • the serum interferon- ⁇ concentrations (e.g. 100-700 pg/mL) refer to non-pegylated embodiments of interferon- ⁇ 2a or interferon- ⁇ 2b (e.g. INTRON® A made by Merck).
  • the interferon- ⁇ can be pegylated.
  • equivalent concentrations can be calculated using art accepted methodologies, for example by calculating the ratio of specific activities and/or molecular weights of: 1) non-pegylated interferon- ⁇ such as INTRON®A and 2) pegylated interferon- ⁇ such as Peglntron® and then using correlations from such analysis to determine appropriate concentrations of, for example, a pegylated interferon-a.
  • Embodiments of the therapeutic regimens disclosed herein include the administration of interferon in combination small molecule therapeutics for patients infected with HBV or HCV, for example ribavirin.
  • interferon in combination small molecule therapeutics for patients infected with HBV or HCV, for example ribavirin.
  • ribavirin in addition to ribavirin, there are a number of other HCV therapeutic agents known in the art in addition to interferon-a.
  • anti-viral agents include for example, but are not limited to, immunomodulatory agents, such as thymosin; VX-950, CYP inhibitors, amantadine, and telbivudine; Medivir's TMC435350, GSK 625433, R1626, ITMN 191, other inhibitors of hepatitis C proteases (NS2-NS3 inhibitors and NS3/NS4A inhibitors); inhibitors of other targets in the HCV life cycle, including helicase, polymerase, and metallopro tease inhibitors; inhibitors of internal ribosome entry; broad-spectrum viral inhibitors, such as IMPDH inhibitors (see, e.g., compounds of U.S. Pat. Nos.
  • immunomodulatory agents such as thymosin; VX-950, CYP inhibitors, amantadine, and telbivudine
  • Embodiments of the methods disclosed herein also include the administration of interferon in combination with small molecule therapeutics for patients infected with HBV.
  • interferon-a 2a in combination with a nucleoside analog such as lamivudine, adefovir dipivoxil, entecavir, telbivudine or tenofovir disproxil in therapeutic regimens designed to treat HBV infection.
  • a nucleoside analog such as lamivudine, adefovir dipivoxil, entecavir, telbivudine or tenofovir disproxil
  • HBV or HCV infected individual is administered a therapeutic agent such as interferon- ⁇ and/ or a small molecule inhibitor and the response to such agents is then observed by monitoring changes in the levels of HBV or HCV nucleotides, and/or viral particles (e.g. viral coat proteins), and/or antibodies to viral antigens, that are detectable in vivo.
  • a therapeutic agent such as interferon- ⁇ and/ or a small molecule inhibitor
  • the response to such agents is then observed by monitoring changes in the levels of HBV or HCV nucleotides, and/or viral particles (e.g. viral coat proteins), and/or antibodies to viral antigens, that are detectable in vivo.
  • an appropriate therapeutic response is associated with decreasing levels of HBV or HCV nucleotides that are detectable in the blood of an infected individual.
  • a therapeutic regimen will reduce this number so that there is no longer any detectable HBV or HCV nucleotides.
  • embodiments of the invention consider additional factors such as a patient's genetic profile and/ or physiology (e.g. Body Mass Index). Illustrating this, a number of genetic polymorphisms are observed to provide information on HBV and HCV infected individuals' response to therapeutic regimens comprising interferon-a and ribavirin. Tables A and B show illustrative single nucleotide polymorphisms associated with HBV and HCV response. In certain embodiments of the invention, information on the SNP genotype is used in methods of determining the dose of interferon-a to be administered to the patient.
  • physiology e.g. Body Mass Index
  • information on the SNP genotype is used in methods of determining a target steady state concentration of interferon- ⁇ to be maintained in a patient's serum.
  • the methods are performed on a plurality of patients infected with hepatitis virus; and the genotype information obtained from the patients is used to stratify patients into different treatment groups (e.g. groups having different IFN dose or regimen duration parameters).
  • treatment groups e.g. groups having different IFN dose or regimen duration parameters.
  • Common SNP analysis methods include hybridization-based approaches (see, e.g., J. G. Hacia, Nature Genet., 1999, 21: 42-47), allele- specific polymerase chain reaction (R. K. Saiki et al., Proc.
  • FIG. 28A illustrates an exemplary generalized computer system 202 that can be used to implement elements the present invention, including the user computer 102, servers 112, 122, and 142 and the databases 114, 124, and 144.
  • the computer 202 typically comprises a general purpose hardware processor 204A and/or a special purpose hardware processor 204B (hereinafter alternatively collectively referred to as processor 204) and a memory 206, such as random access memory (RAM).
  • processor 204 a general purpose hardware processor 204A and/or a special purpose hardware processor 204B
  • memory 206 such as random access memory (RAM).
  • RAM random access memory
  • the computer 202 may be coupled to other devices, including input/ output ( ⁇ / O) devices such as a keyboard 214, a mouse device 216 and a printer 228.
  • the computer 202 operates by the general purpose processor 204A performing instructions defined by the computer program 210 under control of an operating system 208.
  • the computer program 210 and/ or the operating system 208 may be stored in the memory 206 and may interface with the user 132 and/ or other devices to accept input and commands and, based on such input and commands and the instructions defined by the computer program 210 and operating system 208 to provide output and results.
  • Output/ results may be presented on the display 222 or provided to another device for presentation or further processing or action.
  • the display 222 comprises a liquid crystal display (LCD) having a plurality of separately addressable liquid crystals. Each liquid crystal of the display 222 changes to an opaque or translucent state to form a part of the image on the display in response to the data or information generated by the processor 204 from the application of the instructions of the computer program 210 and/or operating system 208 to the input and commands.
  • the image may be provided through a graphical user interface (GUI) module 218A.
  • GUI graphical user interface
  • the GUI module 218A is depicted as a separate module, the instructions performing the GUI functions can be resident or distributed in the operating system 208, the computer program 210, or implemented with special purpose memory and processors.
  • Some or all of the operations performed by the computer 202 according to the computer program 110 instructions may be implemented in a special purpose processor 204B.
  • the some or all of the computer program 210 instructions may be implemented via firmware instructions stored in a read only memory (ROM), a programmable read only memory (PROM) or flash memory in within the special purpose processor 204B or in memory 206.
  • the special purpose processor 204B may also be hardwired through circuit design to perform some or all of the operations to implement the present invention.
  • the special purpose processor 204B may be a hybrid processor, which includes dedicated circuitry for performing a subset of functions, and other circuits for performing more general functions such as responding to computer program instructions.
  • the special purpose processor is an application specific integrated circuit (ASIC).
  • the computer 202 may also implement a compiler 212 which allows an application program 210 written in a programming language such as COBOL, C++, FORTRAN, or other language to be translated into processor 204 readable code. After completion, the application or computer program 210 accesses and manipulates data accepted from 1/ O devices and stored in the memory 206 of the computer 202 using the relationships and logic that was generated using the compiler 212.
  • the computer 202 also optionally comprises an external communication device such as a modem, satellite link, Ethernet card, or other device for accepting input from and providing output to other computers.
  • instructions implementing the operating system 208, the computer program 210, and the compiler 212 are tangibly embodied in a computer- readable medium, e.g., data storage device 220, which could include one or more fixed or removable data storage devices, such as a zip drive, floppy disc drive 224, hard drive, CD-ROM drive, tape drive, etc.
  • the operating system 208 and the computer program 210 are comprised of computer program instructions which, when accessed, read and executed by the computer 202, causes the computer 202 to perform the steps necessary to implement and/or use the present invention or to load the program of instructions into a memory, thus creating a special purpose data structure causing the computer to operate as a specially programmed computer executing the method steps described herein.
  • Computer program 210 and/or operating instructions may also be tangibly embodied in memory 206 and/or data communications devices 230, thereby making a computer program product or article of manufacture according to the invention.
  • article of manufacture “program storage device” and “computer program product” as used herein are intended to encompass a computer program accessible from any computer readable device or media.
  • a user computer 102 may include portable devices such as medication infusion pumps, analyte sensing apparatuses, cellphones, notebook computers, pocket computers, or any other device with suitable processing, communication, and input/ output capability.
  • Fig. 28B presents a specific illustrative embodiment system 10 for performing methods disclosed herein.
  • the interferon-a may be administered at a dosing rate Q(t) 12 from an infusion device 11 including, but not limited to, a pump, a depot, an infusion bag, or the like.
  • the interferon-a serum concentration 14, represented as C(t) may be determined by sampling a patient's blood by assay or sensor 16, and communicated to a controller 18, as represented by a concentration feedback loop 20.
  • the system 10 may also include a viral load feedback loop 22.
  • patient's viral load 24, represented as V(t) may be determined by sampling patient's blood by assay or sensor 26 and may be communicated to the controller 18. Based on C(t), V(t) or both, controller 18 may calculate the dosing rate 12, which may then be adjusted if necessary either automatically by the controller or manually by an individual administering the therapy. In addition, patient-specific pK parameters 13 and pD parameters 15 may be determined from this data.
  • the controller 18 may be a conventional process controller such as a PID controller, one can also utilize an adaptive model predictive process controller or model reference adaptive control.
  • a model predictive controller may be programmed with mathematical models of a "process" to predict "process" response to proposed changes in the inputs. These predictions are then used to calculate appropriate control actions. In response to control actions, the model predictions are continuously updated with measured information from the "process" to provide a feedback mechanism for the controller.
  • the mathematical models may be continuously optimized to match the performance of the "process.”
  • the controller 18 may be programmed with patient-specific pK or pD parameters, population or subpopulation averages, or a combination thereof together with pharmacokinetic and pharmacodynamic models to calculate the dosing rate necessary to achieve desired clinical outcome.
  • the controller continuously processes the data received from the feedback loops to optimize the dosing rate based on a patient's response to the therapy.
  • the controller 18 may also manipulate the pharmacokinetic and pharmacodynamic parameters, as well as the mathematical models based on concentration and viral load data to adopt or customize the models for individual patients and specific conditions.
  • the controller 18 may use patient-specific pharmacokinetic or pharmacodynamic parameters, population or subpopulation averages, or combination thereof together with pharmacokinetic, pharmacodynamic, or viral kinetic models to calculate the dosing rate for desired efficacy based on C(t), V(t) or both.
  • pK refers to the physical pharmacokinetic system of a real patient.
  • the parameter pK' 19 refers to the pharmacokinetic model and parameter values used by the controller to describe pK, and which may be drawn from the real patient, population, or subpopulation averages. Similar notation is used for pD, C, V and Q.
  • a given patient is assumed to have a set of individual pharmacokinetic parameters, represented as pK, and thus actual efficacy may be represented as a function of concentration, which is a function of the dosing rate Q(t).
  • the controller 18 may use pharmacokinetic and pharmacodynamic models to calculate the suitable dosing rate for desired efficacy based on the concentration or other physiological characteristic data. Such models are known and are disclosed in, for example, Bonate, P.L. (2006). Pharmacokinetic- Pharmacodynamic Modeling and Simulation. New York, Springer Science&Business Media; Andrew H Talal, et al. (2006).
  • embodiments of the invention can also examine, a level of alanine transaminase or aspartate transaminase in plasma of the patient; a genotype or quasispecies of the hepatitis virus; a patient's prior medical treatment history; and/ or a presence or degree of a side effect that results from the first therapeutic regimen.
  • the therapeutic agent comprises interferon-a
  • In vivo samples e.g. blood, serum, plasma, tissue etc.
  • samples can be assayed for interferon- ⁇ concentrations using a variety of different methods known in the art.
  • One suitable example is an electrochemiluminescence-based assay and an ORIGEN analyzer (IGEN International, Inc. Gaithersburg, MD) as disclosed for example in Obenauer- Kutner et al., Journal of Immunological Methods, Volume 206, Issues 1-2, 7 August 1997, Pages 25-33.
  • Other methods used in the art include those disclosed for example in Niewold et al., Genes Immun.
  • ELISA kits designed to provide quantitative assays of interferon- ⁇ concentrations in serum (e.g.
  • 100-700 pg/mL are commercially available from vendors, including for example the Human IFN-alpha Platinum ELISA CE available from Bender MedSystems (e.g. Product # BMS216CE) and The Human IFN alpha colorimetric ELISA Kit (Serum Samples) available from Thermo Scientific Life Science Research Products (e.g. Product # 411101).
  • Bender MedSystems e.g. Product # BMS216CE
  • Human IFN alpha colorimetric ELISA Kit serum Samples
  • Thermo Scientific Life Science Research Products e.g. Product # 411101
  • interferon- ⁇ concentrations in human serum samples can be quantified using a ligand-binding assay that can be developed and validated for the COPE-HCV Study using current regulatory standards for quantitative bioanalysis of proteins (see, e.g., Desil et al., Pharm Res 2003;20(l l):1885-900).
  • the PhoenixTM NCA object can be used to characterize the IFN levels that are observed during the 2 weeks following the initiation of continuous INTRON A therapy. This analysis will calculate the values of several parameters.
  • the serum interferon AUC for each subject can be calculated over 0 hour -14 day nominal study time interval.
  • the Linear Trapezoidal linear Interpolation method can be used to calculate these AUC parameters.
  • IFN concentration vs. nominal study time data can be used to calculate AUC without interpolation.
  • the AUC value will reported as "missing" for a given subject and time interval if either of the following criteria are met: 1) one or both of the integration time interval concentration measurements are missing, or 2) there are less than 3 measured concentrations within the integration time interval (including end-points).
  • t and t z are the beginning and the end of the integration time interval, respectively [hr]. illustrative time intervals and AUC calculation methods that can be employed for this analysis are described herein.
  • the maximum observed concentration over a time interval ⁇ [ max ] ; 2 can be determined using the NCA operational object. Illustrative time intervals that can be employed for this analysis are described herein. Percent Fluctuation
  • the percent fluctuation ( PF ⁇ 2 ), as defined by the following Equation, can be calculated for the 24 hour- 14 day nominal study time interval.
  • C° ⁇ 2 and C°* ⁇ 2 are the maximum and minimum observed IFN concentrations over the time interval from t to t z .
  • the minimum observed concentration over a time interval [C m; -ford] f 2 j ean be determined using the NCA operational object.
  • OAS 2', 5'- oligoadenylate synthetase
  • PD pharmacodynamic
  • OAS expression levels can be measured, for example, using a radioimmunoassay (RIA) kit commercially available from the Eiken Chemical Company (Japan).
  • RIA radioimmunoassay
  • Neopterin is a biosynthetic precursor of a factor secreted by stimulated macrophages (see, e.g., Quiroga et al., Dig Dis Sci 1994;39(l l):2485-96) and, in embodiments of the invention, its levels can be measured in serum samples as a PD marker. Neopterin levels can be measured using an EIA (enzyme immunoassay) kit available from B.R.A.H.M.S. (Germany) and distributed in the U.S. by ALPCO.
  • EIA enzyme immunoassay
  • neopterin is a marker of immune system activation (see, e.g. Hoffman et al., Inflamm. res. 52 (2003) 313-321; and Murr et al., Current Drug Metabolism, 2002, 3, 175-187).
  • neopterin production in all three CSID arms compared to the control PEG arm at both 4 and 12 weeks.
  • Increased neopterin in CSID versus PEG provides further evidence for using CSID for HBV therapy.
  • samples were drawn at Baseline, Day 3 and Week 1, 2, 4, 8 and 12.
  • Neopterin concentrations were measured by ELISA and IL28B genotypes were determined by RT-PCR.
  • Time- averaged neopterin response from individual baseline was calculated using non-compartmental methods. E through 4 and 12 weeks was significantly (p ⁇ 0.01, Kruskal-WaUis) greater for each of the 3 CSID arms vs. the PEG arm (Fig. 25).
  • CSID dose did not have a significant effect on E avg (p>0.05).
  • CSID arms did not significantly change through 12 versus 4 weeks (paired t-test). Baseline neopterin did not vary significantly with treatment arm or IL28B. IL28B was not found to have a significant effect on E through 4 and 12 weeks.
  • CSID Compared to PEG-IFN-2b, CSID achieved an enhanced neopterin response in hepatitis C subjects that was sustained through 12 weeks of therapy. This finding provides evidence that CSID is potent activator of cellular immunity and has utility in treating both chronic hepatitis B & C infections.
  • Embodiments of the invention also provide articles of manufacture and kits including for example pump elements (e.g. one or more disposable pump elements), and/or pump apparatuses (e.g. a disposable pump apparatus), in combination with reagents useful for performing methods of the invention.
  • embodiments of the invention include kits comprising an infusion pump apparatus (e.g. a disposable infusion pump) that allows medical personnel to deliver interferon- ⁇ to a subject, in combination with reagents that allow the personnel to obtain interferon- ⁇ serum concentration measurements from the subject following initiation of the therapeutic regimen (e.g. anti- interferon- ⁇ antibodies, interferon- ⁇ standards and the like).
  • an infusion pump apparatus e.g. a disposable infusion pump
  • reagents that allow the personnel to obtain interferon- ⁇ serum concentration measurements from the subject following initiation of the therapeutic regimen (e.g. anti- interferon- ⁇ antibodies, interferon- ⁇ standards and the like).
  • kits provide a combination of elements useful to characterize a pharmacokinetic
  • kits of the invention comprise a single use and/or disposable infusion apparatus designed to deliver interferon- ⁇ to a patient for a limited period of time, for example not more than 7, 5, 4, 3, 2 or 1 days.
  • pump elements and/ or the complete pump apparatus are disposed of after this period of use.
  • the infusion apparatus comprises a micropump and/or a tubing-free system such as the Medingo® tube-free, detachable micropump.
  • the disposable infusion apparatus is a patch pump type apparatus including an adhesive portion that is used to affix the pump to the skin of a subject (see, e.g., U.S. patent application No. 20090259176, the contents of which are incorporated by reference).
  • the disposable infusion apparatus is a infusion device with linear peristaltic pump, for example one comprising: a base that contacts a patient's skin; a reservoir arranged to contain interferon- ⁇ to be delivered beneath a patient's skin, the reservoir having an outlet through which the interferon- ⁇ flows; a flexible conduit communicating with the outlet of the reservoir; and a pump that causes the interferon- ⁇ to flow down the conduit at to the patient (see, e.g., U.S. Patent Application No. 20080097324, the contents of which are incorporated by reference).
  • the disposable infusion apparatus does not include one or more components typically found on reusable infusion pumps, for example a display showing infusion data, a processor, a program code storage unit, or a replaceable battery.
  • the kits further comprise reagents used in interferon- ⁇ plasma or serum concentration measurements such as anti-interferon-a antibodies, interferon-a standards and the like.
  • Such kits can include for example, ELISA plates and/or reagents designed to provide quantitative assays of interferon-a concentrations in serum (e.g. 100-700 pg/mL, 10-70 IU/mL etc.).
  • kits further comprise reagents adapted to measure amounts of hepatitis B or Hepatitis C in vivo, for example, one or more anti-hepatitis B antibodies or primers specific for the Hepatitis B genome, one or more anti-hepatitis C antibodies or primers specific for the Hepatitis C genome and the like.
  • reagents adapted to measure amounts of hepatitis B or Hepatitis C in vivo, for example, one or more anti-hepatitis B antibodies or primers specific for the Hepatitis B genome, one or more anti-hepatitis C antibodies or primers specific for the Hepatitis C genome and the like.
  • PCT/US2010/54755 International Publication No. WO 2011/059824
  • PCT/US2010/44146 International Publication No. WO 2011/014882
  • PCT/US2009/038617 International Publication No. WO 2009/120991
  • PCT/US2009/060121 International Publication No. WO 2010/047974
  • PCT/US2008/078843 International Publication No. WO 2009/046369
  • All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/ or materials in connection with which the publications are cited.
  • EXAMPLE 1 - SERUM INTERFERON MEASUREMENTS DURING THE FIRST WEEK OF CONTINUOUS INTERFERON ALPHA-2B WITH ORAL RIBAVIRIN PREDICTS RVR AND THERAPY DISCONTINUATION IN PATIENTS WITH CHRONIC HCV-1
  • PK pharmacokinetics
  • PD pharmacodynamics
  • PEG-IFNs standard-of-care pegylated-interferons
  • IFN interferon
  • COPE-HCV is an ongoing Phase II clinical study investigating three doses (80, 120, 160 klU/kg/day, corresponding to 6, 9, 12 MlU/day for a 75-kg patient) of CSID with oral RBV versus a PEG-IFN-a-2b control (1.5 ⁇ g/kg/week with RBV) in therapy-naive subjects chronically infected with HCV genotype 1.
  • Eligible subjects were randomized in a 1:1:1:1 ratio to receive weekly PEG-IFN-a-2b (Peglntron ®, Merck, Whitehouse Station, NJ) injections or 1 of 3 weight-based doses (80, 120, 160 klU/kg/day) of non-pegylated IFN-a-2b (Intron A®, Merck) as a continuous subcutaneous IFN-a-2b delivery therapy (CSID) delivered by an external, wearable pump (Paradigm® 722, Medtronic, Minneapolis, MN) for a planned 48 weeks; all study arms included oral weight-based RBV (Rebetol®, Merck).
  • CCD subcutaneous IFN-a-2b delivery therapy
  • Serum IFN concentrations were quantified using ligand-binding assays specifically developed and validated for IFN-a-2b and PEG-IFN-a-2b using current regulatory standards (see, e.g. DeSilva B, et al. Recommendations for the bioanalytical method validation of ligand-binding assays to support pharmacokinetic assessments of macromolecules. Pharm Res 2003;20:1885-1900).
  • the validated lower limit of quantification (LLOQ) for IFN-oc-2b and PEG-IFN-oc-2b are 5.0 and 10 IU/mL, respectively.
  • substitution values of 0 and LLOQ/2 were used, respectively.
  • Plasma HCV RNA levels were measured by RT-PCR (COBAS® AmpliPrep/COBAS® TaqMan® HCV Test, version 1.0, or equivalent, Roche).
  • the assay has a validated LLOQ of 43 IU/mL and lower limit of detection (LLOD) of 18 IU/mL.
  • LLOQ 43 IU/mL
  • LLOD lower limit of detection
  • results ⁇ LLOQ and > LLOD a substitution value of (LLOD+LLOQJ/2 was used.
  • results ⁇ LLOD (“undetectable") a substitution value of LLOD/2 was used.
  • missing HCV RNA results were imputed for a nominal time point only if the preceding and succeeding values were both ⁇ LLOD.
  • neopterin was quantified using an enzyme immunoassay (B.R.A.H.M.S., Germany) with a validated LLOQ and ULOQ of 2 and 250 nmol/L, respectively.
  • OAS was quantified via a radioimmunoassay (Eiken Chemical Company, Japan) with a validated LLOQ and ULOQ of 10 and 810 pmol/dL, respectively.
  • IFN exposure variables for individual subjects in the 3 CSID arms were calculated using non-compartmental analysis (Phoenix WinNonlin Version 6.1, Pharsight, Inc., Cary, NC): area-under-the-curve (AUC), time-averaged concentration (C ⁇ ), maximum observed concentration (C ⁇ ), percent fluctuation (PF%), and minimum concentration (C mm ). IFN concentration vs. time data was not corrected for individual baseline values.
  • AUC, C avg , and C. w ere calculated over nominal study time intervals of Baseline- Week 4 and Baseline-Week 12.
  • the following Equation describes how C was calculated over a given time interval from t to / 2 .
  • PF% and C mm were calculated over nominal study time intervals from Day 3- Week 4 and Day 3-Week 12.
  • the pre-dose Baseline time-point was not included to limit the characterization of the stability of serum IFN levels to a time period concomitant with IFN therapy.
  • the following Equation describes how PF% was calculated over a given time interval fro
  • IFN exposure variables were not calculated for PEG-IFN subjects because of the infrequent sampling schedule relative to the once-weekly dosing period and the known temporal fluctuation of IFN levels resulting from once-weekly bolus administration of PEG-IFN-a-2b (see, e.g. Glue P, et al. Pegylated interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group. Clin Pharmacol Ther 2000;68:556-567). PD Response Variables
  • virologic response HCV RNA ⁇ LLOD, or "undetectable”
  • viral decay decline in log 10 HCV RNA from individual baseline
  • time-averaged changes from individual baseline
  • E ⁇ in neopterin and OAS levels in serum discontinuation of therapy for any reason other than treatment futility (as a measure of tolerability).
  • Rapid virologic response RVR
  • cEVR complete early virologic response
  • E for neopterin and OAS was calculated through 4 and 12 weeks, using non- compartmental analysis methods analogous to the calculation of C for IFN.
  • Discontinuation before 12 weeks for any reason other than lack of efficacy was included as catch-all general measure of reduced safety and tolerability.
  • Dose dependence and proportionality of selected IFN exposure variables on weight-based dose was assessed by a power model, fit to the exposure variable data via linear regression (see, e.g. Gough K, et al. Assessment of Dose Proportionality: Report from the Statisticians in the Pharmaceutical Industry/Pharmacokinetics UK Join Working Party. Drug Information Journal 1995;29:1039-1048).
  • a 95% CI was calculated for the model parameter ⁇ .
  • Each 95% CI for ⁇ was inspected for the inclusion of 1, as evidence of dose-proportionality, and 0, as evidence of dose-independence. Linearity of the regressions was further evaluated through the significance of a quadratic term in the regression model.
  • the proportions of subjects with selected categorical PD responses were calculated for each treatment arm using the number of mITT subjects as the denominator. Differences in categorical efficacy rates between the PEG-IFN arm and each CSID arm were explored by calculating 95% CI's of the difference between two proportions, and p-values were calculated using the normal approximation to the binomial distribution.
  • a multivariate logistic regression analysis via backward selection, was performed with an exit p-value of 0.05 to assess the ability of: 1) selected Week 4 IFN exposure variables to predict RVR, 2) selected Week 12 exposure variables to predict cEVR, and 3) selected Week 4 exposure variables to predict discontinuation before Week 12. Only the CSID arms were included. Since a Week 4 serum IFN measurement was required by the prospective data exclusion rule to calculate the Week 4 exposure variables, the analysis of discontinuation vs. IFN exposure variables effectively considered discontinuations between Weeks 4 and 12.
  • baseline characteristics were included as covariates in the multivariate logistic regression: age, gender, baseline HCV RNA level, fibrosis category (no/minimal fibrosis, portal fibrosis, bridging fibrosis, cirrhosis), IL28B group (CC, CT, TT, missing genotype), race (black/hispanic vs. not black/hispanic), and HCV genotype with all selected Week 4 or Week 12 IFN exposure variables.
  • MW1-IFN concentration remained a statistically significant predictor of RVR (with baseline viral load and IL28B status) and discontinuation (with gender).
  • Subjects with MW1-IFN concentrations ⁇ 32.8 IU/mL had a 39% probability of attaining RVR, while subjects below this value had a 5% chance of attaining RVR.
  • Subjects with MW1-IFN concentrations > 33.2 IU/mL had a 42% probability of discontinuation, while subjects below this value had a 9% chance of discontinuation (Table 1).
  • the median serum IFN levels from the CSID and PEG-IFN arms are plotted in Fig. 1.
  • the highest median serum IFN concentration (34.6 IU/mL) for the PEG-IFN control arm occurred at the visit (Day 3) scheduled to occur approximately midway between weekly bolus injections.
  • the median IFN concentrations in the PEG-IFN arm are ⁇ 15 IU/mL and below the medians for the CSID arms.
  • the IFN levels for the CSID arms appear to converge towards the 12 week time point.
  • One possible explanation for this convergence is that subjects self-selected for a dose with improved tolerability through down-dosing or discontinuation. This observation motivated the selection of discontinuation before Week 12 as a PD response variable in the PD relationship analysis.
  • the stability of serum IFN levels resulting from CSID therapy was characterized by the PF% of serum IFN concentrations for individual subjects from Day 3-Week 4 and Day 3-Week 12. The calculated values for PF% are summarized in Fig. 2. The values of PF% for the combined CSID arms from Day 3 through Week 4 and Week 12 of therapy are compared with historical controls in Fig. 3.
  • CSID 12 are presented in Fig. 4.
  • the enhanced viral kinetics of CSID relative to PEG- IFN with increasing dose is illustrated as the maximum line intensity is seen to shift from the upper right-hand to the lower left-had corner of the sub-panels, moving from PEG- IFN to CSID 80, to CSID 120, and to CSID 160.
  • the number and proportion of subjects in each treatment arm who exhibited selected PD responses are reported in Table 3, where statistically significant differences between individual CSID arms vs. the PEG-IFN arm are denoted.
  • the number of mITT subjects in each study arm are provided in the column headings.
  • the RVR rate monotonicaUy increases with increasing randomized dose (p ⁇ 0.05, Cochran-Armitage test).
  • the discontinuation rate through Week 4 was similar across the 3 CSID arms (11%-16%), with the CSID 80 arm being significantly larger than the PEG-IFN control (0%; p ⁇ 0.05).
  • the proportions of subjects with undetectable HCV RNA are similar across the 3 CSID arms (42%-44%) and trend higher than the PEG-IFN control (25%, p>0.05).
  • the cEVR rate of the CSID 80 (60%) arm is significantly higher (p ⁇ 0.01) than the cEVR rate of the PEG-IFN control (25%).
  • the discontinuation rate through Week 12 for the CSID 120 (33%) and 160 (38%) arms are significantly higher than the PEG-IFN control (11%, p ⁇ 0.05).
  • the apparent trends in the cEVR and cumulative discontinuation rates are not statistically significant (p > 0.20, Cochran-Armitage test).
  • Table 4 Contingency Tables for Week 4 as a univariate predictor for RVR and Therapy Discontinuation.
  • Time-averaged neopterin response (neopterin £ a3 ⁇ 4 ) was significantly higher in each of the CSID arms verses the PEG-IFN arm through 4 and 12 weeks (p ⁇ 0.01), but CSID dose did not have a significant effect (p>0.05).
  • the percent fluctuation (PF%) of IFN-a-2b administered according to its label (3 MIU TIW; see, e.g. INTRON A. (Interferon-alfa-2b, recombinant) for Injection Product Insert. In. Schering-Plough (now Merck); 2008) was estimated using data published by Glue and co-workers (see, e.g. Glue P, et al. Pegylated interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group. Clin Pharmacol Ther 2000;68:556-567) for a single bolus during the fourth week of therapy.
  • Percent fluctuation was calculated using the mean values reported in Table I from Glue and co-workers (see, e.g. Glue P, et al. Pegylated interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group. Clin Pharmacol Ther 2000;68:556-567) and the Equation:
  • the percent fluctuation of PEG-IFN-a-2a administered according to its label was estimated using the PK model and model parameters reported by Dahari and co-workers (see, e.g. Dahari H, Affonso de Araujo ES, et al. Pharmacodynamics of PEG-IFN-a-2a in HIV/HCV co-infected patients: Implications for treatment outcomes. Journal of Hepatology 2010;53:460-467).
  • the percent fluctuation of PEG-IFN-a-2b administered according to its label was estimated using the PK model and model parameters reported by Talal and co-workers (see, e.g. Talal AH, et al. Pharmacodynamics of PEG-IFN alpha differentiate HIV/HCV coinfected sustained virological responders from nonresponders. Hepatology 2006;43:943-953).
  • PK parameters (k e , k a and FD/ V d ) were provided in the publication for week 1 and week 2 of therapy for 21 individual subjects.
  • PF% was calculated from 3 days through 4 weeks and 3 days through 12 weeks of therapy using individual IFN concentration vs. time profiles calculated using the published PK model and PK parameters derived from week 2 of therapy.
  • the first premise of CSID therapy for chronic HCV infection is that continuous subcutaneous infusion of IFN can achieve circulating IFN concentrations that are relatively stable compared to repeated bolus injections of IFN or PEG-IFN.
  • the second premise of CSID is that the relatively stable levels of non-pegylated IFN, with its high level of biopotency and unrestricted volume of distribution, will result in enhanced PD response.
  • the PK results presented herein support the first premise.
  • the PF% through week 4 of CSID is significantly less than historical controls for IFN TIW, IFN-a-2b QW, and IFN-a-2a QW (Fig. 3, left).
  • the PF% of CSID is significantly less than IFN TIW and PEG-IFN-a-2b QW, while the PF% of CSID is similar to PEG-IFN- a-2a QW (Fig. 3, right).
  • PEG-IFN-oc-2a with its relatively large and more branched polyethylene glycol moiety, has a sub-optimal PD profile as it has been shown to require approximately 8-fold higher circulating IFN concentrations than PEG-IFN-a- 2b to achieve 50% viral suppression in patients who achieve SVR (see, e.g. Talal AH, et al. Pharmacodynamics of PEG-IFN alpha differentiate HIV/HCV coinfected sustained virological responders from nonresponders.
  • the PK results presented here support the feasibility of CSID therapy in that IFN exposure variables were found to be dose-proportionate through 4 ⁇ C avg , C max ⁇ C m consult) and 12 ⁇ C avg , C ma ⁇ weeks of therapy.
  • Dose-proportionality is an ideal characteristic of any drug therapy, as it implies that the pharmacokinetics are amenable to control, the importance of which is highlighted by the critical values for Week 4 C mm discussed below.
  • the half-life of IFN ⁇ 4 hours, see, e.g. Zeuzem S, et al. Pharmacokinetics of Peginterferons. SEMINARS IN LIVER DISEASE 2003:023), these results position CSID as a rapidly adjustable and individually tailorable therapy for the treatment of chronic hepatitis C.
  • the PD results presented here support the second premise of CSID, in that subjects in the CSID arms exhibited both accelerated viral kinetics (Fig. 4) and an increased proportion of subjects with undetectable HCV RNA (Table 3), relative to the PEG-IFN control. Furthermore, time-averaged neopterin response (E ⁇ was significantly higher at 4 and 12 weeks in each of the CSID arms versus the PEG-IFN control (p ⁇ 0.01), providing evidence that CSID at the investigated doses results in increased activation of cellular immunity relative to PEG-IFN (see, e.g. Hoffmann G, et al. Potential role of immune system activation-associated production of neopterin derivatives in humans. Inflamm Res 2003;52:313-321).
  • the critical IFN concentration for attaining RVR of 32.8 IU/ mL is 4-fold greater than the mean C mm reported for week 4 of PEG-IFN-a-2b therapy ( ⁇ 8 IU/ mL).
  • the serum IFN concentrations after Day 3 represent an upper bound for the true C mm for each week for therapy, and it is notable that the median values ( ⁇ 15 IU/mL, Fig. 1) are below the critical values of 32.8 and 60.7 IU/mL.
  • results presented here provide evidence that continuous subcutaneous delivery of non-pegylated IFN will result in more constant circulating levels of more biopotent IFN as compared to current standard of care and suggest a role for CSID in the rapidly changing hepatitis B & C therapy landscapes.
  • the relatively stable IFN levels achieved by CSID are associated with accelerated viral kinetics and an increased proportion of patients achieving undetectable HCV RNA.
  • EXAMPLE 2 SINGLE SERUM INTERFERON MEASUREMENT DURING THE FIRST WEEK OF CONTINUOUS INTERFERON ALPHA-2B WITH ORAL RIBAVIRIN PREDICTS RVR AND THERAPY DISCONTINUATION IN PATIENTS WITH CHRONIC HCV-1
  • COPE-HCV is an on-going, Phase II, multi-center, randomized, open-label, active-control, dose-ranging study being conducted in the U.S.
  • the study includes a 4-arm randomized evaluation of 3 dose levels (80, 120 or 160 klU/kg/day) of IFN-a-2b delivered via continuous subcutaneous (SC) infusion compared with PEG- IFN-a-2b given as once-weekly SC injections.
  • SC subcutaneous
  • MWl-IFN mid-week 1 IFN
  • Rapid virological response was defined as undetectable HCV RNA ( ⁇ LLOD) after 4 weeks of therapy.
  • Discontinuation was defined as study discontinuation within the first 12 weeks for any reason other than failing efficacy continuation criteria.
  • Critical values for predictive cutoff levels for MWl-IFN were determined by a single branching of univariate recursive partitioning and were confirmed by inspection of ROC curves. Fisher's exact test was used to calculate statistical significance of contingency tables.
  • MWl-IFN was initially found to be a significant predictor for both RVR and discontinuation within the first 12 weeks among subjects in the three CSID arms, as assessed by univariate logistic regression.
  • MWl-IFN concentration remained a statistically significant predictor of RVR (with baseline viral load and IL28B status) and discontinuation (with gender).
  • Subjects with MWl-IFN concentrations ⁇ 32.8 IU/mL had a 39% probability of attaining RVR, while subjects below this value had a 5% chance of attaining RVR.
  • Subjects with MWl-IFN concentrations ⁇ 33.2 IU/mL had a 42% probability of discontinuation, while subjects below this value had a 9% chance of discontinuation (Table C).
  • Figure 24B shows a detailed relationship of significant predictors of RVR or discontinuation from multivariate logistic regression analyses.
  • the two significant continuous variables (baseline HCV RNA and MWl-IFN concentration) are plotted against each other for each combination of the two significant categorical variables - IL28B genotype and gender.
  • the critical value found for the achievement of RVR is 32.8. Genotypes are grouped into CC, CT, TT or unknown, which are indicated by "NA" in the figure.
  • the Entrez SNP database provides a library of single nucleotide polymorphisms such as those disclosed in Mbarek et al.
  • the sequences of various polymorphism are cataloged with a SNP designation (e.g. rs2856718 and rs7453920).
  • Illustrative SNP sequences obtained using such SNP designations as a query are provided in Table A.
  • Table A the polymorphic nucleotide in these SNP sequences is bracketed (nucleotide position 27).
  • databases such as the Entrez Global Query Cross-Database Search System provide search engines that allow users to search databases at the National Center for Biotechnology Information (NCBI) website.
  • NCBI National Center for Biotechnology Information
  • the Entrez SNP database provides a library of single nucleotide polymorphisms such as those disclosed in Ge et al., Nature. 2009; 461(7262): 399-401.
  • the sequences of various polymorphism are cataloged with a SNP designation (e.g. rsl2979860).
  • Illustrative SNP sequences obtained using such SNP designations (e.g. rsl2979860) as a query are provided in Table 2.
  • Table 2 the polymorphic nucleotide in these SNP sequences is bracketed (nucleotide position 27).
  • rsl2979860 as a query are provided in Table B.
  • Table B the polymorphic nucleotide in these SNP sequences is bracketed (nucleotide position 27).
  • CTGAGCTCCATGGGGCAGCTTTTATC [C/T ] CTGACAGAAGGGCAGTCCCAGCTGA ( SEQ ID NO: 10)
  • Table C Subjects with MWl-IFN concentrations > 33.2 IU/mL had a 42% probability of discontinuation, while subjects below this value had a 9% chance of discontinuation.
  • Table D Summary statistics of IFN exposure variables and viral kinetics for the first 4 weeks of continuous IFN therapy. Results are aggregated for the 3 dosing arms of continuous IFN. Data from 33 subjects were included in this analysis. Differences in employeed data sets for different variables account for the disparity in N.

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Abstract

L'invention porte sur des méthodologies et sur des systèmes concernant l'administration d'interféron-a. Des analyses de données d'essai clinique montrent que des observations de profils pharmacocinétiques d'interféron-a à la suite de son administration, par l'intermédiaire d'un dispositif de perfusion continue, peuvent être mises en corrélation avec les réponses virales à cet agent thérapeutique. De telles informations peuvent être utilisées, par exemple pour optimiser le traitement d'individus infectés par les virus de l'hépatite B et C.
PCT/US2012/026792 2011-02-25 2012-02-27 Procédés et systèmes utilisant des profils pharmacocinétiques et pharmacodynamiques dans régimes thérapeutiques d'interféron-alpha WO2012116370A1 (fr)

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Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997040028A1 (fr) 1996-04-23 1997-10-30 Vertex Pharmaceuticals Incorporated Derives d'uree agissant comme inhibiteurs de l'enzyme impdh
US5807876A (en) 1996-04-23 1998-09-15 Vertex Pharmaceuticals Incorporated Inhibitors of IMPDH enzyme
WO1998040381A1 (fr) 1997-03-14 1998-09-17 Vertex Pharmaceuticals Incorporated Inhibiteurs de l'enzyme impdh
US6054472A (en) 1996-04-23 2000-04-25 Vertex Pharmaceuticals, Incorporated Inhibitors of IMPDH enzyme
WO2000056331A1 (fr) 1999-03-19 2000-09-28 Vertex Pharmaceuticals Incorporated Inhibiteurs de l'enzyme impdh
US20080097324A1 (en) 2006-05-31 2008-04-24 Seattle Medical Technologies Disposable infusion device with linear peristaltic pump
WO2009046369A2 (fr) 2007-10-05 2009-04-09 Medtronic, Inc. Contrôle pharmacocinétique pour l'administration optimisée d'interféron
WO2009120991A2 (fr) 2008-03-27 2009-10-01 Medtronic, Inc. Outils pharmacocinétiques et pharmacodynamiques destinés à définir des régimes thérapeutiques spécifiques à un patient
US20090259176A1 (en) 2008-04-09 2009-10-15 Los Gatos Research, Inc. Transdermal patch system
WO2010047974A1 (fr) 2008-10-23 2010-04-29 Medtronic, Inc. Système automatique de commande de dose pour le traitement de l'hépatite c en utilisant des pompes d'infusion
WO2011014882A1 (fr) 2009-07-31 2011-02-03 Medtronic, Inc. Administration continue par voie sous-cutanée d'interféron-α à des patients infectés par le virus de l'hépatite c
WO2011059824A2 (fr) 2009-10-29 2011-05-19 Medtronic, Inc. Méthodes et matériels pour des régimes thérapeutiques contre l'hépatite c optimisés

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6344465B1 (en) 1996-04-23 2002-02-05 Vertex Pharmaceuticals, Incorporated Inhibitors of IMPDH enzyme
US5807876A (en) 1996-04-23 1998-09-15 Vertex Pharmaceuticals Incorporated Inhibitors of IMPDH enzyme
US6054472A (en) 1996-04-23 2000-04-25 Vertex Pharmaceuticals, Incorporated Inhibitors of IMPDH enzyme
WO1997040028A1 (fr) 1996-04-23 1997-10-30 Vertex Pharmaceuticals Incorporated Derives d'uree agissant comme inhibiteurs de l'enzyme impdh
WO1998040381A1 (fr) 1997-03-14 1998-09-17 Vertex Pharmaceuticals Incorporated Inhibiteurs de l'enzyme impdh
US6498178B2 (en) 1999-03-19 2002-12-24 Vertex Pharmaceuticals Incorporated Inhibitors of IMPDH enzyme
WO2000056331A1 (fr) 1999-03-19 2000-09-28 Vertex Pharmaceuticals Incorporated Inhibiteurs de l'enzyme impdh
US20080097324A1 (en) 2006-05-31 2008-04-24 Seattle Medical Technologies Disposable infusion device with linear peristaltic pump
WO2009046369A2 (fr) 2007-10-05 2009-04-09 Medtronic, Inc. Contrôle pharmacocinétique pour l'administration optimisée d'interféron
WO2009120991A2 (fr) 2008-03-27 2009-10-01 Medtronic, Inc. Outils pharmacocinétiques et pharmacodynamiques destinés à définir des régimes thérapeutiques spécifiques à un patient
US20090259176A1 (en) 2008-04-09 2009-10-15 Los Gatos Research, Inc. Transdermal patch system
WO2010047974A1 (fr) 2008-10-23 2010-04-29 Medtronic, Inc. Système automatique de commande de dose pour le traitement de l'hépatite c en utilisant des pompes d'infusion
WO2011014882A1 (fr) 2009-07-31 2011-02-03 Medtronic, Inc. Administration continue par voie sous-cutanée d'interféron-α à des patients infectés par le virus de l'hépatite c
US20110027229A1 (en) * 2009-07-31 2011-02-03 Medtronic, Inc. Continuous subcutaneous administration of interferon-alpha to hepatitis c infected patients
WO2011059824A2 (fr) 2009-10-29 2011-05-19 Medtronic, Inc. Méthodes et matériels pour des régimes thérapeutiques contre l'hépatite c optimisés

Non-Patent Citations (70)

* Cited by examiner, † Cited by third party
Title
A. C. SYVANEN ET AL., GENOMICS, vol. 8, 1990, pages 684 - 692
ANDREW H TALAL ET AL.: "Pharmacodynamics of PEG-IFN a Differentiate HIV/HCV Coinfected Sustained Virological Responders from Nonresponders.", HEPATOLOGY, vol. 43, no. 5, 2006, pages 943 - 953, XP002632822, DOI: doi:10.1002/HEP.21136
ARIMURA ET AL., NEUROVIROL, vol. 13, no. 4, 2007, pages 364 - 72
BONATE, P.L.: "Pharmacokinetic-Pharmacodynamic Modeling and Simulation", 2006, SPRINGER SCIENCE&BUSINESS MEDIA
BONNEM ET AL., J BIOL RESPONSE MOD, vol. 3, no. 6, 1984, pages 580 - 98
BUDD; CANCER, CHEMOTHER PHARMACOL, vol. 12, no. 1, 1984, pages 39 - 42
CALICETI ET AL., DIGESTIVE AND LIVER DISEASE, vol. 36, no. 3, 2004, pages 334
CALICETI P, DIGESTIVE AND LIVER DISEASE, vol. 36, 2004, pages S334
CHRISTEFF ET AL., EUROPEAN JOURNAL OF CLINICAL INVESTIGATION., vol. 32, no. 1, January 2002 (2002-01-01), pages 43 - 50
DAHARI ET AL., IIEPATOLOGY, vol. 46, no. 1, 2007, pages 16 - 21
DAHARI ET AL., J THCOR BIOL, vol. 247, no. 2, 2007, pages 371 - 81
DAHARI H ET AL.: "Pharmacodynamics of PEG-IFN-?-2a in HIV/HCV co-infected patients: Implications for treatment outcomes", JOURNAL OF HEPATOLOGY, vol. 53, 2010, pages 460 - 467
DAHARI I I ET AL.: "Pharmacodynamics of PEG-TFN-a-2a in HTV/HCV co-infected patients: Implications for treatment outcomes", JOURNAL OF HEPATOLOGY, vol. 53, 2010, pages 460 - 467
DAHARI II; AFFONSO DE ARAUJO ES ET AL.: "Pharmacodynamics of PEG-IFN-?-2a in HIV/HCV co-infected patients: Implications for treatment outcomes", JOURNAL OF HEPATOLOGY, vol. 53, 2010, pages 460 - 467
DESIL ET AL., PHARM RES, vol. 20, no. 11, 2003, pages 1885 - 900
DESILVA B ET AL.: "Recommendations for the bioanalytical method validation of ligand-binding assays to support pharmacokinetic assessments of macromolecules", PHARM RES, vol. 20, 2003, pages 1885 - 1900
DIXIT ET AL., NATURE, vol. 432, no. 7019, 2004, pages 922
FCLD, NATURE, vol. 436, no. 7053, 2005, pages 967 - 72
FERNANDEZ ET AL., J CLIN GASTROENTEROL., vol. 30, no. 2, 2000, pages 181 - 6
GABRIELSSON, J.; D. WEINER: "Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts and Applications", 2000, PHARMACEUTICAL PRESS
GABRIELSSON, J.; D. WEINER: "Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts and Applications", 2000, SWEDISH PHARMACEUTICAL PRESS
GE ET AL., NATURE, vol. 461, no. 7262, 2009, pages 399 - 401
GLUE P ET AL.: "Pegylated interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data", HEPATITIS C INTERVENTION THERAPY GROUP. CLIN PHARMACOL THCR, vol. 68, 2000, pages 556 - 567, XP001010037, DOI: doi:10.1067/mcp.2000.110973
GLUE P ET AL.: "Pegylated interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data", HEPATITIS C INTERVENTION THERAPY GROUP. CLIN PHARMACOL THER, vol. 68, 2000, pages 556 - 567, XP001010037, DOI: doi:10.1067/mcp.2000.110973
GLUE P ET AL.: "Pegylated interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group", CLIN PHARMACOL THCR, vol. 68, 2000, pages 556 - 567
GLUE P: "Pcgylatcd interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Tntervention Therapy Group", CLIN PHARMACOL THER, vol. 68, 2000, pages 556 - 567
GLUE, CLIN PHARMACOL THCR, vol. 68, no. 5, 2000, pages 556 - 6
GOUGH K: "Assessment of Dose Proportionality: Report from the Statisticians in the Pharmaceutical Industry/Pharmacokinetics UK Join Working Party", DRUG TNFORMATION JOURNAL, vol. 29, 1995, pages 1039 - 1048
GUIDOTTI ET AL., J VIROL., vol. 68, no. 3, March 1994 (1994-03-01), pages 1265 - 70
HAMLEN C ET AL: "PK/PD modeling of continuous interferon therapy for HCV", HEPATOLOGY, WILLIAMS AND WILKINS, BALTIMORE, MD, US, vol. 48, no. 4 Suppl.S, 1 October 2008 (2008-10-01), pages 534A, XP002602733, ISSN: 0270-9139 *
HOFFMAN ET AL., INFLAMM. RES., vol. 52, 2003, pages 313 - 321
HOFFMANN G ET AL.: "Potential role of immune system activation-associated production of neopterin derivatives in humans", INFLAMM RES, vol. 52, 2003, pages 313 - 321
J. G. HACIA, NATURE GCNCT., vol. 21, 1999, pages 42 - 47
JOHAN GARBIELSSON; DAN WEINER: "PHARMACOKINETIC & PHARMACODYNAMIC DATA ANALYSIS: CONCEPTS & APPLICATIONS", 2000, SWEDISH PHARMACEUTICAL PRESS, pages: 161 - 177
KOSKINAS ET AL., MED VIROL., vol. 81, no. 5, 24 March 2009 (2009-03-24), pages 848 - 852
LAM ET AL., DIGESTIVE DISEASES AND SCIENCES, vol. 42, no. 1, 1997, pages 178 - 85
LI ET AL., BMC INFECT DIS., vol. 11, 9 June 2011 (2011-06-09), pages 165
LI-ZHE XU, J. GEN. VIROL., vol. 75, 1994, pages 2393 - 98
MALAQUARNERA, EUR J GASTROENTEROL HEPATOL., vol. 12, no. 8, August 2000 (2000-08-01), pages 937 - 9
MCCARTHY ET AL., GASTROENTEROLOGY, vol. 138, no. 7, 2010, pages 2307 - 14
MCHUTCHISON JG ET AL.: "Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection", N ENGL J MED, vol. 361, 2009, pages 580 - 593
MCI IUTCHISON JG ET AL.: "Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection", N ENGL J MED, vol. 360, 2009, pages 1827 - 1838
MURR ET AL., CURRENT DRUG METABOLISM, vol. 3, 2002, pages 175 - 187
NEUMANN ET AL., SCIENCE, vol. 282, no. 5386, 1998, pages 103 - 7
NIEWOLD ET AL., GENES TMMUN., vol. 8, 2007, pages 492 - 502
OBENAUER-KUTNCR ET AL., JOURNAL OF IMMUNOLOGICAL METHODS, vol. 206, no. 1-2, 7 August 1997 (1997-08-07), pages 25 - 33
PERELSON ET AL., HEPATOLOGY, vol. 42, no. 4, 2005, pages 749 - 754
PERRILLO, AM J GASTROENTEROL., vol. 106, no. 10, October 2011 (2011-10-01), pages 1774 - 6
PIRISI, DIGESTIVE DISEASES AND SCIENCES, vol. 42, no. 4, 1997, pages 767 - 7771
PODEVIN ET AL., J JHEPATOL., no. 2, 1997, pages 265 - 71
POORDAD F ET AL.: "Boceprevir for Untreated Chronic HCV Genotype 1 Infection", NEW ENGLAND JOURNAL OF MEDICINE, vol. 364, 2011, pages 1195 - 1206, XP002687767, DOI: doi:10.1056/NEJMoa1010494
POWERS ET AL., LIVER TRANSPL, vol. 12, no. 2, 2006, pages 207 - 16
POWERS ET AL., SEMIN LIVER DIS, vol. 23, no. 1, 2003, pages 13 - 18
QUIROGA ET AL., DIG DIS SCI, vol. 39, no. 11, 1994, pages 2485 - 96
R. K. SAIKI ET AL., PROC. NATL. ACAD. SCI. USA, vol. 86, 1989, pages 6230 - 6234
RAUCH ET AL., GASTROENTEROLOGY, vol. 138, no. 4, 2010, pages 1338 - 45
ROCHE: "PEGASYS. (peginterferon-alfa-2a) Product Insert", PHARMACEUTICALS, 2008
SCHENKER S ET AL: "Activity and tolerance of a continuous subcutaneous infusion of interferon-alpha2b in patiens with chronic hepatitis C", JOURNAL OF INTERFERON AND CYTOKINE RESEARCH, MARY ANN LIEBERT, NEW YORK, NY, US, vol. 17, no. 11, 1 November 1997 (1997-11-01), pages 665 - 670, XP002903597, ISSN: 1079-9907 *
SHUDO ET AL., J VIRAL HEPAT, vol. 15, no. 5, 2008, pages 379 - 82
SIBBITT ET AL., ARTHRITIS & RHEUMATISM, vol. 28, no. 6, 2005, pages 624 - 629
SIMMONDS ET AL., J. GEN. VIROL., vol. 74, 1994, pages 661 - 668
STERLING ET AL., DIG DIS SCI., vol. 53, no. 5, 2007, pages 1375 - 82
TALAL AH ET AL.: "Pharmacodynamics of PEG-IFN alpha differentiate HIV/HCV coinfected sustained virological responders from nonresponders", HEPATOLOGY, vol. 43, 2006, pages 943 - 953, XP002632822, DOI: doi:10.1002/HEP.21136
TALAL ET AL., HCPATOLOGY, vol. 43, no. 5, 2006, pages 943 - 953
TANAKA ET AL., NAT GENET., vol. 41, no. 10, 2009, pages 1105 - 9
THOMAS ET AL., NATURE, vol. 461, no. 7265, 2009, pages 798 - 801
U. LANDEGREN ET AL., SCIENCE, vol. 24, 1988, pages 1077 - 1080
V. LYAMICHEV ET AL., NATURE BIOTECHNOL., vol. 17, 1999, pages 292 - 296
W. M. HOWELL ET AL., NATURE NIOTECHNOL., vol. 17, 1999, pages 87 - 88
WIEGAND ET AL., ANTIVIR THER., vol. 13, no. 4, 2008, pages 547 - 54

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