WO2009134637A1

WO2009134637A1 - Piperazine-based ccr5 antagonist tablet dosage form

Info

Publication number: WO2009134637A1
Application number: PCT/US2009/041196
Authority: WO
Inventors: Sheetal R. Muley; Wing-Kee Philip Cho
Original assignee: Schering Corporation
Priority date: 2008-04-28
Filing date: 2009-04-21
Publication date: 2009-11-05
Also published as: AR071394A1; PE20091886A1; CL2009000965A1; TW200948363A

Abstract

Tablets containing 1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-[4-[2-methoxy-1(R)-[4-(trifluoromethyl)phenyl]ethyl]-3-(S)-methyl-1-piperazinyl]-4-methyl-piperi dine or a pharmaceutically acceptable salt thereof are disclosed. Methods of making such tablets with satisfactory processability are also disclosed. In addition, methods for treating HIV as well as inflammatory diseases with an antagonist of chemokine (C-C motif) receptor 5 (CCR5) are disclosed.

Description

PIPERAZEVE-BASED CCR5 ANTAGONIST TABLET DOSAGE FORM

Field of the Invention

The present invention relates to tablets comprising l-[(4,6-dimethyl-5- pyrimidinyl)carbonyl]-4-[4-[2-methoxy-l(R)-[4-(trifluoromethyl)phenyl]ethyl]-3-(S)-methyl- l-piperazinyl]-4-methyl-piperidine or a pharmaceutically acceptable salt thereof. The invention also relates to methods of treating human immunodeficiency virus (HIV) infection as well as inflammatory diseases using such tablets and methods of preparing such tablets.

Background of the Invention

Discussion or citation of a reference herein shall not be construed as an admission that such reference is prior art to the present invention.

The global health crisis caused by HIV, the causative agent of Acquired Immunodeficiency Syndrome (AIDS), is unquestioned, and while recent advances in drug therapies have been successful in slowing the progression of AIDS, there is a need for new drug therapies in light of the emergence of drug-resistant HIV strains known to be transmissible as well as the growing number of multi-class drug resistance patients. In fact, as of 2004, in countries with broad access to antiretrovirals, drug-resistant HIV strains were detected in up to 20% of newly infected individuals. Likewise, the emergence of drug-resistant HIV strains has led to customized drug therapies, so-called, "optimized background therapy" (OBT) for individual patients based on the results of resistance testing to one or more antiretrovirals among the different antiretro viral classes of nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). Furthermore, there is a need for more tolerable drug therapies that result in greater patient convenience and improved compliance (e.g., oral, solid dosage form, low pill burden, once-a day or twice-a-day regimen, less adverse effects) to reduce the potential for development of new drug-resistant HIV strains.

It has been reported that the chemokine (C-C motif) receptor 5 (CCR5) gene plays a role in resistance to HIV infection. HIV infection begins by attachment of the virus to a target cell membrane through interaction with the cellular receptor CD4 and a secondary chemokine co-receptor molecule, and proceeds by replication and dissemination of infected cells through the blood and other tissue. There are various chemokine receptors, but for macrophage-tropic HIV, believed to be the key pathogenic strain that replicates in vivo in the early stages of infection, the principal chemokine receptor required for the entry of HIV into a cell is CCR5. Therefore, interfering with the interaction between the viral receptor and CCR5 can block HIV entry into the host cell. Moreover, as CCR5 antagonists target an extracellular mechanism of HIV, they are less likely to produce drug-resistant HIV strains and also more likely to be effective against current drug-resistant HIV strains that overcome intracellular mechanisms of antiretroviral action against HIV.

CCR5 has also been reported to mediate cell transfer in inflammatory diseases such as arthritis, rheumatoid arthritis, atopic dermatitis, psoriasis, asthma and allergies. Consequently, antagonists of CCR5 are believed to be useful in the treatment of such diseases, and in the treatment of other inflammatory diseases or conditions such as inflammatory bowel disease, multiple sclerosis, solid organ transplant rejection and graft v. host disease. 1 - [(4, 6-dimethyl-5 -pyrimidinyl)carbony1 ] -4- [4-[2-methoxy- 1 (R)- [4- (trifluoromethyl)phenyl]ethyl]-3-(S)-methyl-l-piperazinyl]-4-methyl-piperidine, referred to herein as Compound I, represented by the following chemical structure:

or a pharmaceutically acceptable salt thereof is a CCR5 antagonist disclosed in U.S. Pat. Nos. 6,391,865 (see, e.g., column 24 to column 25 and column 35 to column 116, Example 29A), the entire disclosure of which is incorporated herein by reference. This CCR5 antagonist binds to the chemokine receptor CCR5 in a manner that effectively blocks ligand binding and receptor signaling on human cells. In addition, it inhibits infection of primary cells by HIV-I isolates that use this receptor by inhibiting viral fusion and entry. l-[(4,6-dimethyl-5- pyrimidinyl)carbonyl]-4-[4-[2-methoxy-l(R)-[4-(trifluoromethyl)phenyl]ethyl]-3-(S)-methyl- l-piperazinyl]-4-methyl-piperidine or a pharmaceutically acceptable salt thereof (also known as "vicriviroc," "SCH 417690," and "SCH D") is currently in late stage clinical trials for oral administration in combination with one or more other antiretroviral agents to patients infected with HIV.

Summary of the Invention

Objectives

To meet the demands for effective drug therapies while reducing the potential for drug- resistant HIV strains, it is imperative to develop drug dosage forms that foster patient compliance (e.g., oral, solid dosage form, low pill burden, once-a-day or twice-a-day dosing). Generally, oral solid dosage forms are preferred for their ease of administration to patients as well as handling and storage. In particular, tablets provide the active pharmaceutical ingredient in a minimum volume per dosage unit thus reducing the pill burden in terms of the number as well as the size of the individual units required for daily administration of an effective amount. In addition, to meet the demands of an increasingly large HIV-positive patient population and reduce the financial burden associated with patient care, it is valuable to develop a robust manufacturing process for such drug dosage forms that allows a large volume to be readily and reliably prepared with satisfactory processability for commercialization.

Summary

The present invention meets the aforementioned objectives or needs for a solid dosage form of Compound I or a pharmaceutically acceptable salt thereof suitable for oral administration as well as a robust manufacturing process for making the same.

In particular, the present invention provides a tablet suitable for oral administration that features up to 20% w/w loading of Compound I or a pharmaceutically acceptable salt thereof. Tablets of the present invention comprise a granulate comprising Compound I or a pharmaceutically acceptable salt thereof suitable for tableting. In a preferred embodiment, tablets of the invention provide sufficiently beneficial pharmacokinetic parameters of Compound I or a pharmaceutically acceptable salt thereof for treatment of HIV patients using once-a-day dosing regimens. Such tablets provide useful pharmacokinetic properties for the treatment of HIV infection in a patient on an optimized background therapy regimen containing PI/r. Such tablets are also useful for treating an inflammatory disease.

The present invention also provides a robust manufacturing process that allows a large volume of tablets of the present invention to be readily and reliably prepared with satisfactory processability for commercialization. In particular, the present invention provides a high shear wet granulation process that produces a large volume of such tablets with satisfactory processability wherein the tablets exhibit no sticking to tooling surfaces and good powder flow from the hopper.

In one aspect the present invention provides a tablet for oral administration comprising a granulate comprising Compound I or a pharmaceutically acceptable salt thereof and a binder, a disintegrant, and a diluent, wherein Compound I or a pharmaceutically acceptable salt thereof comprises 10% to 20% by weight of the tablet.

In one embodiment, the pharmaceutically acceptable salt of Compound is an acid addition salt formed using hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, methanesulfonic acid or other mineral and carboxylic acids well known to those in the art. In one preferred embodiment, the pharmaceutically acceptable salt of Compound is an acid addition salt formed using maleic acid, i.e., the maleate salt of Compound I.

In certain preferred embodiments, the amount of Compound I or a pharmaceutically acceptable salt is equivalent to 24.6 mg free base of Compound I. In one preferred embodiment, the pharmaceutically acceptable salt of Compound I is a maleate salt at a 30 mg dose.

In certain embodiments, the binder is microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural gum, synthetic gum, polyvinylpyrrolidone or povidone (PVP), pregelatinized starch, HPC, HPMC, or a combination of two or more thereof. In one preferred embodiment, the binder is PVP.

In certain embodiments, the disintegrant is sodium starch glycolate, carboxymethylcellulose or a salt thereof, croscarmellose or a salt thereof, crospovidone or a salt thereof, methylcellulose, microcrystalline cellulose, one- to six-carbon alkyl-substituted HPC, starch, pregelatinized starch, sodium alginate, or a combination of two or more thereof. In one preferred embodiment, the disintegrant is a croscarmellose salt.

In certain embodiments, the diluent is lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, dibasic calcium phosphate dehydrate, or a combination of two or more thereof. In one preferred embodiment, the diluent is microcrystalline cellulose. In another preferred embodiment, the diluent a combination of microcrystalline cellulose and lactose monohydrate.

In another embodiment, the tablet further comprises an extragranular excipient such as a diluent, a disintegrant, a lubricant, or a combination of two or more thereof.

In another embodiment, the tablet further comprises an extragranular excipient which is lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, dibasic calcium phosphate dehydrate, or a combination of two or more thereof. In one preferred embodiment, the tablet further comprises an extragranular excipient which is microcrystalline cellulose.

In certain embodiments, the tablet further comprises an extragranular excipient which is sodium starch glycolate, carboxymethylcellulose or a salt thereof, croscarmellose or a salt thereof, crospovidone or a salt thereof, methylcellulose, microcrystalline cellulose, one- to six- carbon alkyl-substituted HPC, starch, pregelatinized starch, sodium alginate, or a combination of two or more thereof. In one preferred embodiment, the tablet further comprises an extragranular excipient which is a croscarmellose salt. In certain embodiments, the tablet further comprises an extragranular excipient which is magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, sodium lauryl sulfate, or a combination of two or more thereof. In one preferred embodiment, the tablet further comprises an extragranular excipient which is magnesium stearate.

In certain embodiments, Compound I or a pharmaceutically acceptable salt thereof comprises 20% by weight of the tablet. In one embodiment, the granulate comprises 65% to 70% by weight of the tablet. In one embodiment, binder comprises 2% to 8% by weight of the tablet. In one embodiment, disintegrant comprises 1% to 6% by weight of the tablet. In one embodiment, diluent comprises 60% to 70% by weight of the tablet. In one embodiment, lubricant comprises 0.25% to 10% by weight of the tablet. In one embodiment, the tablet further comprises a surfactant, a glidant or a combination of two or more thereof.

In another aspect the present invention provides a tablet comprising a granulate of Compound I or a pharmaceutically acceptable salt thereof which provides a mean steady-state AUC of Compound I that is about 6210 ng-hr/ml when administered at a dose equivalent to 24.6 mg free base of Compound I once-a-day to a patient on an optimized background therapy regimen containing PI/r. The present invention also encompasses tablets which are similarly bioavailable such that the relative mean steady-state AUC of Compound I is within 80% to 125% of 6210 ng-hr/ml, that is within the range from about 4968 ng-hr/ml to about 7763 ng- hr/ml, when administered at a dose equivalent to 24.6 mg free base of Compound I once-a-day to a patient on an optimized background therapy regimen containing PI/r. In one embodiment, the tablet provides a mean steady-state AUC of Compound I which is at least 80% of 6210 ng- hr/ml, that is at least 4968 ng-hr/ml, when administered at a dose equivalent to 24.6 mg free base of Compound I once-a-day to a patient on an optimized background therapy regimen containing PI/r. In a certain embodiment, the tablet provides a mean steady-state AUC of Compound I which is at least 6210 ng-hr/ml when administered at a dose equivalent to 24.6 mg free base of Compound I once-a-day to a patient on an optimized background therapy regimen containing PI/r.

In another aspect the present invention provides a tablet comprising a granulate of Compound I or a pharmaceutically acceptable salt thereof which provides a mean steady-state Cmin of Compound I that is at least 200 ng/ml when administered at a dose equivalent to 24.6 mg free base of Compound I to a patient on an optimized background therapy regimen containing PI/r. In one preferred embodiment, the tablet is administered once-a-day. In another embodiment, the tablet is administered twice-a-day.

In one embodiment, the tablet provides a mean steady-state Cmax of Compound I that is at least 297 ng/ml at a mean Tmax that is in the range from about 1 hour to about 3 hours when administered at a dose equivalent to 24.6 mg free base of Compound I once-a-day to a patient on an optimized background therapy regimen containing PI/r.

In on embodiment, the tablet provides a mean steady-state Cmax of Compound I that is about 372 ng/ml when administered at a dose equivalent to 24.6 mg free base of Compound I once-a-day to a patient on an optimized background therapy regimen containing PI/r. The present invention also encompasses tablets which are similarly bioavailable such that the relative mean steady-state Cmax of Compound I is within 80% to 125% of 372 ng/ml, that is within the range from about 297 ng/ml to about 465 ng/ml, when administered at a dose equivalent to 24.6 mg free base of Compound I once-a-day to a patient on an optimized background therapy regimen containing PI/r. In one embodiment, the tablet provides 297 ng/ml when administered at a dose equivalent to 24.6 mg free base of Compound I once-a-day to a patient on an optimized background therapy regimen containing PI/r. In a certain embodiment, the tablet provides a mean steady-state AUC of Compound I which is at least 372 ng/ml when administered at a dose equivalent to 24.6 mg free base of Compound I once-a-day to a patient on an optimized background therapy regimen containing PI/r.

In certain preferred embodiments, the amount of Compound I or a pharmaceutically acceptable salt is equivalent to 24.6 mg free base of Compound I. In one embodiment, the pharmaceutically acceptable salt of Compound I is a maleate salt at a 30 mg dose.

In certain embodiments, the granulate further comprises a binder, a disintegrant, and a diluent.

In one embodiment, the granulate is prepared by a process comprising: (a) dry-blending:

(i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) a disintegrant, and a diluent to provide a first dry-blended powder; (b) agglomerating the first dry-blended powder prepared in Step "a" in a high shear granulator using a granulating solution comprising water and a binder;

(c) forming a wet milled granulate by wet-milling the agglomerate prepared in Step "b"; (d) forming a dried granulate by drying the wet milled granulate from Step "c"; and

(e) dry-milling the dried granulate from Step "d".

Those skilled in the art will appreciate that the optimal range of the granulating solution target spray rate will vary according to the batch size, and can be determined by routine experimentation. In one embodiment of a pilot scale batch, the granulating solution target spray rate is in the range of about 270 g/min to about 390 g/min. In another embodiment, the granulating solution target spray rate is about 330 g/min. In one embodiment of a pilot scale batch, the target wet massing time is in the range of about 30 seconds to about 6 minutes. In another embodiment, the target wet massing time is in the range of about 30 seconds to about 4 minutes. In another embodiment, the target wet massing time is about 1 minute. In one aspect the invention provides a method for treating HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of any of the tablets of the present invention. In one embodiment, the method further comprises administering at least one other antiretroviral agent.

In one aspect the invention provides a method for treating HIV infection in a patient comprising administering to a patient in need thereof a therapeutically effective amount of any of the tablets of the present invention in conjunction with an antiretroviral therapy regimen. In one preferred embodiment, the therapy regimen is an optimized background therapy regimen. In one aspect the invention provides a method for treating HIV infection in a patient on an optimized background therapy regimen containing PI/r comprising administering to the patient in need thereof a therapeutically effective amount of any of the tablets of the present invention. In one embodiment, the optimized background therapy regimen containing PI/r comprises darunavir. In certain embodiments, darunavir is administered at a dose of 600 mg twice a day (BID). In one embodiment, the patient is antiretroviral treatment naϊve. In another embodiment, the patient is antiretroviral treatment experienced. In one aspect the invention provides a method for treating HIV infection in an antiretroviral experienced adult patient comprising co-administration to the antiretroviral experienced adult patient in need thereof a therapeutically effective amount of any of the tablets of the present invention with PI/r. In one aspect the invention provides a method for treating an inflammatory disease comprising administering to a patient in need thereof a therapeutically effective amount of any of the tablets of the present invention.

Detailed Description of the Drawing

Figure 1 shows a process flow for the manufacture of exemplary tablets of the maleate salt of Compound I by a high-shear wet granulation process.

Detailed Description of the Invention

In order that the invention herein described may be fully understood, the following detailed description is set forth.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. The materials, methods and examples are illustrative only, and are not intended to be limiting. All publications, patents and other documents mentioned herein are incorporated by reference in their entirety.

The term "vicriviroc" refers to l-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-[4-[2- methoxy-l(R)-[4-(trifluoromethyl)phenyl]ethyl]-3-(S)-methyl-l-piperazinyl]-4-methyl- piperidine or a pharmaceutically acceptable salt thereof.

The term "protease inhibitor/ritonavir (PI/r)" refers to a treatment regimen that includes ritonavir with another protease inhibitor. For example, a treatment regimen that includes the protease inhibitor darunavir in combination with ritonavir. In one embodiment, ritonavir is administered below its therapeutic dose as a protease inhibitor, that is below 600 mg twice-a- day (e.g., 100 mg/day).

"AUC" as used herein means, for any given active agent, the "area under the plasma concentration-time curve" from dosing of the active agent to a time point, calculated by the trapezoidal rule. AUC is a parameter showing the cumulative plasma concentration of an active agent over time, and is an indicator of the total amount and availability of an active agent in the plasma. Unless the time point is otherwise defined, AUC is understood to cover the timepoint from time zero to 24 hours. "Cmax" as used herein refers to the maximum observed plasma concentration for a given active agent.

"Cmin" as used herein refers to the trough plasma concentration for a given active agent predose (0 hr). The term "wet massing time" used herein refers to the time from the end of granulating solution addition until the end of the agglomeration step wherein mixing between the dry- blended first powder and the granulating solution occurs.

The term "treating" or "treatment" is intended to mean mitigating or alleviating one or more of the symptoms associated with the recited condition or disease. The preparation of Compound I and pharmaceutically acceptable salts thereof has been described in U.S. Pat. No. 6,391,865 (see, e.g., column 24 to column 25 and column 35 to column 116, Example 29A) which is incorporated by reference in its entirety. A specific process for the preparation, inter alia, of the maleate salt of Compound I is disclosed in U.S. Pat. No. 6,943,251, incorporated herein by reference in its entirety. In one embodiment, the pharmaceutically acceptable salt of Compound is an acid addition salt formed using hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, methanesulfonic acid or other mineral and carboxylic acids well known to those in the art. In one preferred embodiment, the pharmaceutically acceptable salt of Compound is an acid addition salt formed using maleic acid.

Exemplary pharmaceutically acceptable salts of Compound I include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bromide, calcium edetate, camphorsulfonate, carbonate, chloride/dihydrochloride, citrate, N₅N- di(dehydroabietyl)ethylenediamine, edetate, 1,2-ethanedisulfonate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, p-glycollamidophenylarsonate, hexylresorcinate, hyclate, hydrobromide, hydrochloride, 2-hydroxyethanesulfonate, hydroxynaphthoate, iodide, lactate, lactobionate, lauryl sulfonate, malate, maleate, mandelate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, nafate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphosphate, polygalacturonate, salicyclate, sodium succinate, stearate, subacetate, succinate, sulfate, tosylate, tannate, tartarate/bitartarate, 8- chlorotheophyllinate, triethiodide, adipate, alginate, aminosalicyclate, anhydromethylenecitrate, arecoline, asparate, bisulfate, butylbromide, camphorate, digluconate, dihydrobromide, disuccinate, glycerophosphate, hemisulfate, hydrofluoride, hydroiodide, methylenebis(salicyclate), naphthalenedisulfonate, oxalate, pectinate, persulfate, phenylethylbarbiturate, picrate, propionate, thiocyanate, undecanoate, acetylaminoacetate, N- acetyl-L-asparaginate, N-acetylcystinate, adamantoate, adipoate, N-alkylsulfamates, anthraquinone-l,5-disulfonate, arabolactansulfate, argininate, aspartate, betaine, carnitine, A- chloro-m-toluenesulfonate, decanoate, diacetyl sulfate, dibenzylethylenediamine, dimethylamine, diguaiacylphosphate, dioctylsulfosuccinate, pamoate, fructose- 1,6- diphosphate, glucose phosphate, L-glutaminate, hydroxynaphthoate, lauryl sulfate, lysine, 2- naphthenesulfonate, octanonate, tannate and theobromine acetate. In one preferred embodiment, the pharmaceutically acceptable salt of Compound I is a maleate salt. Tablets

In one specific embodiment, the present invention provides tablet dosage forms comprising a tablet that includes a) Compound I or a pharmaceutically acceptable salt thereof; b) a binder; c) a diluent; and d) a disintegrant. In certain embodiments, the tablet may include additional binders, diluents and/or disintegrants. In certain embodiments, the tablet comprises granules comprising Compound I or a pharmaceutically acceptable salt thereof; the binder(s); the diluent(s); and the disintegrant(s). In certain embodiments, the granules comprise 65% to 75% by weight of the tablet. In certain such embodiments, and independently or in conjunction with the weight percentage of granules in the tablet, the granules comprise 25% to 33% by weight of Compound I or a pharmaceutically acceptable salt thereof, 60% to 70% by weight of diluent, 1% to 6% by weight of disintegrant and 2% to 8% by weight of binder. In certain embodiments, the tablet comprises at least 10% by weight of Compound I or a pharmaceutically acceptable salt thereof. In certain embodiments, the tablet comprises about 20% by weight of Compound I or a pharmaceutically acceptable salt thereof. In certain embodiments, the tablet further comprises an extragranular component comprising one or more diluents, one or more disintegrants, one or more lubricants or a combination of two or more thereof. Binders are generally used to impart cohesive qualities to the tablet dosage form.

Examples of binders include, without limitation, microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, povidone (PVP), pregelatinized starch, HPC, HPMC, and a combination of two or more thereof. In a preferred embodiment, the binder is povidone. Binders may make up about 2% to 8% by weight of the tablet, such as 3% to 5%, and are typically only present in the granules. In a preferred embodiment, the binder is povidone and is present at about 4% by weight of the tablet.

Examples of disintegrants include, without limitation, sodium starch glycolate; carboxymethylcellulose, including its sodium and calcium salts; croscarmellose, including its salts such as croscarmellose sodium; crospovidone, including its sodium salt; methylcellulose; microcrystalline cellulose; one- to six-carbon alkyl-substituted HPC; starch; pregelatinized starch; sodium alginate; and a combination of two or more thereof. In a preferred embodiment, the disintegrant is a croscarmellose salt.

The disintegrant may make up about 1% to about 25% of the tablet, or more typically, about 1% to about 6% of the tablet, based on weight. In one preferred embodiment, the disintegrant is about 4% by weight of the tablet. In certain embodiments, 25% to 75% by weight of the disintegrant is granular and 25% to 75% by weight of the disintegrant is extragranular. In particular embodiments, 40% to 60% by weight of the disintegrant is granular and 40% to 60% by weight of the disintegrant is extragranular such as where the disintegrant is approximately evenly divided between the granules and the extragranular portion of the tablet. In a preferred embodiment, about 50% of the disintegrant is present granularly and about 50% of the disintegrant is present extragranularly.

One or more diluents may make up the balance of the tablet formulation. Examples of diluents include, without limitation, lactose monohydrate, spray-dried lactose monohydrate, anhydrous lactose, and the like; mannitol; xylitol; dextrose; sucrose; sorbitol; microcrystalline cellulose; starch; dibasic calcium phosphate dihydrate; and a combination of two or more thereof. Diluents may make up 40% to 85% by weight of the tablet, such as 50% to 75% or 60% to 70%. In certain embodiments, the diluents is microcrystalline cellulose, lactose or a combination of two or more thereof. A preferred mixture of diluents is microcrystalline cellulose and lactose (e.g., lactose monohydrate). In certain embodiments, the lactose is present only in the granules and the microcrystalline cellulose is present both in the granules and extragranularly. In certain such embodiments, the diluent mixture consists of 40% to 65% by weight lactose monohydrate, 5% to 10% by weight granular microcrystalline cellulose and 20% to 40% by weight extragranular microcrystalline cellulose (i.e., the tablet comprises 35% to 45% by weight lactose monohydrate, 20 to 30% by weight extragranular microcrystalline cellulose and 2% to 8% by weight granular microcrystalline cellulose).

An exemplary tablet of the invention therefore includes 15% to 25% by weight of Compound I or a pharmaceutically acceptable salt thereof, 35% to 45% by weight lactose monohydrate, 25% to 35% by weight microcrystalline cellulose, 2% to 6% by weight croscarmellose sodium, 2% to 6% by weight povidone and 1% to 3% by weight magnesium stearate.

In one preferred embodiment, the tablet of the invention includes 20% by weight of Compound I or a pharmaceutically acceptable salt thereof, 40% by weight lactose monohydrate, 30% by weight microcrystalline cellulose distributed in a granular to extragranular ratio of about 1 to about 5, 4% by weight croscarmellose sodium distributed in a granular to extragranular ratio of about 1 to about 1, 4% by weight povidone, and 2% by weight magnesium stearate. In a specific preferred embodiment, the pharmaceutically acceptable salt of Compound I is a maleate salt.

In addition to the active agent, binder(s), disintegrant(s), and diluent(s) the tablets of the invention may include one or more surfactant(s), glidant(s), lubricant(s) or a combination of two or more thereof.

Examples of suitable surfactants, include, without limitation, SLS, polysorbate 80 and a combination or two or more thereof. When present, surfactants may make up about 0.2% to about 5% of the tablet by weight.

Examples of suitable glidants include, without limitation, silicon dioxide, talc and a combination of two or more thereof. When present, glidants may make up about 0.2% to about 1% of the tablet by weight.

Examples of suitable lubricants include, without limitation, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, sodium lauryl sulfate, and a combination of two or more thereof. In a preferred embodiment, the lubricant is magnesium stearate. Lubricants, when present may make up about 0.25% to about 10%, or more typically, about 1% to about 3% of the tablet, and are typically present only extragranularly.

In some embodiment, it is preferred to supply the tablet with a film coating, preferably a film coating comprising a hydroxypropylmethyl cellulose-based (HPMC-based) coating material such as Opadry II Green® or Opadry II White®. The film coating may add, for example, 1% to 10% by weight to the tablet. Typically, the film coating adds 4% to 8% by weight to the tablet. In one preferred embodiment, the film coating adds 6% by weight to the tablet. Preparation of Tablets

Tablets of the invention can be prepared by a variety of suitable wet granulation, including high shear wet granulation, techniques. A compressible particulate suitable for tableting that contains Compound I or a pharmaceutically acceptable salt thereof can be prepared using the process diagramed in Scheme I below:

Scheme I

(a) Dry-blend:

(i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) a granular excipient (e.g., diluent, disintegrant) to provide a first dry-blended powder

(b) Agglomerate the first dry-blended powder from Step "a" in a high shear granulator using a granulating solution comprising water and a binder

(c) Form a wet milled granulate by wet-milling the agglomerate prepared in Step "b"

(d) Form a dried granulate by drying the wet milled granulate from Step "c"

(e) Dry mill the dried granulate from Step "d"

(f) Dry-blend to homogeneity:

To Tablet Press

(i) Dried milled granulate from Step "e"; and (ii) optionally, an extragranular excipient (e.g., lubricant, diluent, disintegrant)

In one example, Compound I or a pharmaceutically acceptable salt thereof and a granular excipient, (e.g., diluent, disintegrant) are dry-blended. In certain embodiments, Compound I or a pharmaceutically acceptable salt thereof is delumped through a 1190 micron screen prior to dry-blending. After intimate blending of the first dry-blended powder, the powder is agglomerated with a granulating solution comprising water and a binder to produce a wet granulate. For example, a binder solution of about 23 % w/v povidone in water. In certain embodiments, wet granulation is carried out under high shear conditions. In one embodiment, suitable for pilot plant scale, the granulating solution target spray rate is in the range of about 270 g/min to about 390 g/min. In another embodiment, the granulating solution target spray rate is 330 g/min. In one embodiment suitable for pilot plant scale, the target wet massing time is in the range of about 30 seconds to about 6 minutes. In another embodiment, the target wet massing time is in the range of about 30 seconds to about 4 minutes. In another embodiment, the target wet massing time is about 1 minute. The agglomerate is then wet milled using a COMIL wet mill. Following wet-milling, the wet granulate is dried. In some embodiments, it is preferred to dry the wet granulate in a fluid bed dryer to a residual moisture content of about 2 wt.% or less. Next, the dried granulate is dry-milled such as through a screen size of 16-18 mesh, to produce a granulate. Next, the granulate is dry-blended to homogeneity with at least one extragranular excipient (e.g., diluent, disintegrant, lubricant). This particulate is suitable for tableting with a compression tableter. The resultant tablet formed, can optionally be film coated.

Useful high-shear, wet granulators include, without limitation, top-mounted high-shear granulators, twin-screw mixers, planetary mixers, high-speed mixers, extruder-spheronizers and the like. For an additional discussion of wet granulators, see M. Summers & M. Aulton, Dosage Form Design and Manufacture 25:364-78 (2d ed., 2001), the complete disclosure of which is herein incorporated by reference.

High-shear wet granulation is a more robust process compared to fluid-bed granulation. Accordingly, a high-shear wet granulation process is preferred as a commercial manufacturing process for tablets of Compound I or a pharmaceutically acceptable salt thereof.

Tablets prepared by this method may have one or more of the following properties. First, tablets prepared by the methods described herein preferably do not stick to typical manufacturing equipment. For example, tablets of the present invention may be prepared on typical manufacturing equipment without the need to treat the equipment itself with a glidant or lubricant and/or the tablets themselves leave a sufficiently small residue amount of material on tableting equipment that the material does not interfere with a typical manufacturing process. Second, the tablets of the invention may be prepared regardless of the particle size of Compound I or a pharmaceutically acceptable salt thereof. For example, in certain embodiments, there is no need to monitor or regulate the proportion of particles of Compound I or a pharmaceutically acceptable salt thereof that are less than 10 microns in diameter.

Notably, the particle size distribution of the maleate salt of Compound I drug substance spans from less than 0.1 μm to greater than 500 μm, indicating a heterogeneous particle population. The maleate salt of Compound I typically exists as fines (0.1 -lμm) primary particles (5-10 μm) and fused aggregated particles (>500 μm). Once crystallized, the drug substance has the tendency to loosely aggregate upon isolation and drying. The drug substance crystallization process consists of multiple delumping steps, which affect the extent of aggregation in the drug substance. The amount of water present in the crystallization slurry is a critical factor in determining the size of primary particles, and has to be controlled within a narrow range of 1.5-2.5% w/w for direct compression of tablets. Moreover, direct compression is ill suited for commercial scale manufacture as sticking to tooling surfaces is often observed. Likewise, roller compaction exhibits some sticking to tooling surfaces and thus is also ill suited for commercial scale manufacture. In contrast, it has been surprisingly discovered that a wide particle size distribution of the maleate salt of Compound I can be processed into a particulate matter suitable for tableting by high shear wet granulation with no sticking to tooling surfaces upon tablet compression.

Notabaly, Figure 1 shows an illustrative example of a process flow for the manufacture of tablets of the maleate salt of Compound I by a high-shear wet granulation process. Combination Therapies

The tablets of this invention may be used in combination with one or more other antiretroviral agents useful in the treatment of HTV. Compound I or a pharmaceutically acceptable salt thereof may be combined with one or more other antiretroviral agents in a single dosage form. Alternatively, Compound I or a pharmaceutically acceptable salt thereof may be administered simultaneously or sequentially with one or more other antiretroviral agents as separate dosage forms. The antiretroviral agents encompassed for use in combination with the vicriviroc of the present invention comprise one or more nucleoside or nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, viral fusion inhibitors, integrase inhibitors, and other antiretroviral agents listed below not falling within these classifications. In particular, the combinations known as HAART (Highly Active Antiretroviral Therapy) are encompassed for use in combination with Compound I or a pharmaceutically acceptable salt thereof. In specific embodiments, the invention encompasses administering any of the tablets of the present invention once-a-day to HIV infected or HTVVHCV co-infected patients on an optimized background therapy regimen containing PI/r.

The term "nucleoside and nucleotide reverse transcriptase inhibitors" ("NRTI" s) as used herein means nucleosides and nucleotides and analogues thereof that inhibit the activity of HIV-I reverse transcriptase, the enzyme which catalyzes the conversion of viral genomic HIV-I RNA into proviral HIV-I DNA.

Typical suitable NRTIs include, but are not limited to, zidovudine (AZT, RETROVIR®); didanosine (ddl, VIDEX®); zalcitabine (ddC, HIVID®); stavudine (d4T, ZERIT®); lamivudine (3TC, EPIVIR); abacavir (1592U89, ZIAGEN®)(see WO96/30025); adefovir dipivoxil [bis(POM)-PMEA, PREVON®]; Iobucavir (BMS-180194)(see EP-0358154 and EP-0736533), a reverse transcriptase inhibitor (in the form of a racemic mixture of BCH- 10618 and BCH-10619); emitricitabine [(-)-FTC] (see U.S. Pat. No. 5,814,639); beta-L-D4C and named beta-L-2',3'-dideoxy-5-fluoro-cytidene (beta-L-FD4); (-)-beta-D-2,6,-diamino- purine dioxolane (DAPD) (see EP 0656778); and Iodenosine (FddA, 9-(2,3-dideoxy-2-fluoro- b-D-threo-pentofuranosyl)adenine). The term "non-nucleoside reverse transcriptase inhibitors" ("NNRTFs) as used herein means non-nucleoside s that inhibit the activity of HIV-I reverse transcriptase.

Suitable NNRTIs include, but are not limited to, nevirapine (BI-RG-587, VIRAMUNE®); delaviradine (BHAP, U-90152, RESCRIPTOR®); efavirenz (DMP-266, SUSTIVA®) (see WO94/03440); PNU- 142721 (a furopyridine-thio-pyrimide); AG- 1549

(formerly Shionogi # S-1153); 5-(3,5-dichlorophenyl)-thio-4-isopropyl-l-(4-pyridyl)methyl- lH-imidazol-2-ylmethyl carbonate (see WO 96/10019); MKC-442 (l-(ethoxy-methyl)-5-(l- methylethyl)-6-(phenylmethyl)-(2,4(lH,3H)-pyrimidinedione) d; and (+)-calanolide A (NSC- 675451) and B, coumarin derivatives (see U.S. Pat. No. 5,489,697). The term "protease inhibitor" ("PI") as used herein means inhibitors of the HIV-I protease, an enzyme required for the proteolytic cleavage of viral polyprotein precursors (e.g., viral GAG and GAG Pol polyproteins), into the individual functional proteins found in infectious HIV-I. HIV protease inhibitors include compounds having a peptidomimetic structure, high molecular weight (7600 daltons) and substantial peptide character, e.g. CRIXIVAN® as well as nonpeptide protease inhibitors e.g., VIRACEPT® .

Suitable PIs include, but are not limited to, darunavir (Prezista™), saquinavir (Ro 31- 8959, INVIRASE®, FORTOUASE®); ritonavir (ABT-538, NORVIR®); indinavir (MK-639, CRIXIVAN®); nelfhavir (AG- 1343, VIRACEPT®); amprenavir (141W94, AGENERASE®); lasinavir (BMS-234475, CGP-61755); DMP-450 (a cyclic urea); BMS-2322623 (an azapeptide); ABT-378; and AG-1549 (an orally active imidazole carbamate, Shionogi #S- 1153).

Other antiretroviral agents include, but are not limited to, hydroxyurea, ribavirin, IL-2, IL- 12, enfuvirtide (FUZEON®) and Yissum Project No. 11607.

The term "antiretroviral agents useful in the treatment of HIV" as used herein means any antiretroviral agent found useful for treating HIV-I infections alone, or as part of multidrug combination therapies, e.g., the HAART triple and quadruple combination therapies. Typical suitable therapies include, but are not limited to multidrug combination therapies such as (i) at least three antiretroviral agents selected from two NRTIs, one PI, a second PI, and one NNRTI; and (ii) at least two antiretroviral agents selected from, NNRTIs and PIs. Typical suitable HAART-- multidrug combination therapies include:

(a) triple combination therapies such as two NRTIs and one PI; or (b) two NRTIs and one NNRTI; and (c) quadruple combination therapies such as two NRTIs, one PI and a second PI or one NNRTI. In treatment of naive patients, it is preferred to start treatment of HIV with the triple combination therapy; the use of two NRTIs and one PI is preferred unless there is intolerance to PIs. Drug compliance is essential. The CD4⁺ and HIV-I-RNA plasma levels should be monitored every 3-6 months. Should viral load plateau, a fourth drug, e.g., one PI or one NKRTI could be added.

Typical antiretroviral multi-drug combination therapies are summarized below:

Antiretroviral Multi-Drug Combination Therapies A. Triple Combination Therapies l. Two NRTIs'+one PI²⁰ 2. Two NRTIs'+one NNRTI³ B. Quadruple Combination Therapies⁴

1. Two NRTIs+one PI+a second PI or one NNRTI C. Alternatives⁵

1. Two IVRTI¹

2. One NRTI⁵+one PI²

3. Two PIs⁶ +-.one NRTI⁷ or NNRTI³

4. One PI² + one NRTI⁷ + one NNRTI³ Footnotes:

¹. One of the following: zidovudine+lamivudine; zidovudine+didanosine; stavudine+lamivudine; stavudine+didanosine; zidovudine+zalcitabine

². Indinavir, nelfinavir, ritonavir or saquinavir soft gel capsules.

³. Nevirapine or delavirdine. 4. See A-M. Vandamne et al Antiretroviral Chemistry & Chemotherapy 9: 187 at p 193-197.

⁵. Alternative regimens are for patients unable to take a recommended regimen because of compliance problems or toxicity, and for those who fail or relapse on a recommended regimen. Double nucleoside combinations may lead to HIV-resistance and clinical failure in many patients. 6. Most data obtained with saquinavir and ritonavir (each 400 mg bid).

¹. Zidovudine, stavudine or didanosine.

Suitable antiretroviral therapies are also described in "Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV- 1 -infected adults and adolescents," Department of Health and Human Services. January 29, 2008; 1-128, incorporated herein by reference.

Agents known in the treatment of rheumatoid arthritis, transplant and graft v. host disease, inflammatory bowel disease and multiple sclerosis, which can be administered in combination with Compound I or a pharmaceutically acceptable salt thereof are as follows: solid organ transplant rejection and graft v. host disease: immune suppressants such as cyclosporine and Interleukin-10 (IL-IO), tacrolimus, antilymphocyte globulin, OKT-3 antibody, and steroids; inflammatory bowel disease: IL-IO (see U.S. Pat. No. 5,368,854), steroids and azulfidine; rheumatoid arthritis: methotrexate, azathioprine, cyclophosphamide, steroids and mycophenolate mofetil; multiple sclerosis: interferon-beta, interferon-alpha, and steroids.

In addition to the above, a therapeutically effective amount of pegylated interferon-alfa may be administered in association with a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof sufficient to lower HIV-I-RNA plasma levels.

Further, the invention provides a method of treating an HIV infection comprising administering in combination a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a DP- 178 polypeptide, or a pharmaceutically acceptable derivative thereof.

Additional combination therapies suitable for use in the methods of the invention are described in US 6,391,865, US 6,689,765, US 2004/0067691, US 2006/0105964, US 6,635,646 and US 2005/0065319, the contents of which are incorporated herein by reference. Pharmaceutical Compositions Compound I may exist in different isomeric forms (e.g., enantiomers, diastereoisomers, atropisomers and rotamers). The invention encompasses tablets which can contain any such isomers, both in pure form and in admixture, including racemic mixtures.

The quantity of Compound I or a pharmaceutically acceptable salt thereof in a unit dose may be varied or adjusted from about 10 mg to about 150 mg, preferably from about 10 mg to about 30 mg according to the particular application. In certain preferred embodiments, the amount of Compound I or a pharmaceutically acceptable salt is equivalent to 24.6 mg free base of Compound I. For the treatment of HIV infection, the quantity of Compound I or a pharmaceutically acceptable salt thereof in a unit dose is preferably 30 mg, especially preferred where the pharmaceutically acceptable salt of Compound I is the maleate salt. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.

The amount and frequency of administration of Compound I or a pharmaceutically acceptable salt thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 20 mg/day to about 100 mg/day, preferably 20 mg/day to 60 mg/day, more preferably about 30 mg/day. In one preferred embodiment, the daily dose of the maleate salt of Compound I is 30 mg/day, equivalent to 24.6 mg free base (Compound I), administered in a single daily dose.

Preferably, Compound I or a pharmaceutically acceptable salt thereof is administered to a HIV-positive patient on an optimized background therapy regimen containing PI/r. More preferably, Compound I or a pharmaceutically acceptable salt thereof is administered at a dose of 30 mg/day to a HIV-positive patient on an optimized background therapy regimen containing PI/r.

The doses and dosage regimen of the NRTIs, NNRTIs, PIs and other agents will be determined by attending clinician in view of the approved doses and dosage regimen in the package insert or as set forth in the protocol taking into consideration the age, sex and condition of the patient and the severity of the HIV-I infection.

While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention. Examples

Exemplary tablet formulations for the maleate salt of Compound I are detailed in Tables 1.1 and 1.2. The robustness of the high-shear wet granulation process was determined by using micronized drug substance (prepared from batch lot A) using various milling/delumping conditions, which represented the worst-case drug substance with respect to particle size distribution (largest proportion of fines and therefore a larger specific surface area). Drug product batch # 7 (Table 1.2), made with micronized drug substance lot B at 10% drug loading, behaved similar to other batches made with "standard" drug substance (batch lot A) in terms of processibility and absence of sticking to punch surfaces. Only drug product batch # 8 and 9 at 15% drug loading, exhibited slight film formation on the tooling surfaces.

Additional exemplary tablet formulations are detailed in Table 2 wherein various excipient ranges were examined. In particular, the ranges and excipients examined are as follows: 1.5% and 2.5% w/w magnesium stearate, 3% and 5% w/w povidone, as well as 2% and 6% w/w croscarmellose sodium. Micronized drug substance (lot C) was employed in order to demonstrate formulation and process robustness under worst conditions of particle size distribution (Q₉o_% < 3 microns). Drug product batch # 18, at 20% drug loading, exhibited slight film formation on the tooling surfaces. Otherwise, no filming or sticking was observed in any of the other exemplary formulations described in Table 2.

Clinical Studies

Clinical Study No. 1

Objectives: (i) To evaluate the safety and tolerability of vicriviroc (specifically, the maleate salt of Compound I) when administered orally at doses of 10 mg BID, 25 mg BID, 50 mg BID for 14 days in HIV-infected subjects, (ii) To determine the multiple-dose pharmacokinetics and viral pharmacodynamics of vicriviroc in HIV infected subjects.

Methodology: This was a randomized, third-party blind (within dose level), placebo- controlled, rising multiple dose study in which 49 subjects infected with HIV-I were assigned to treatment with vicriviroc 10 mg twice-a-day (BID), 25 mg BID, or 50 mg BID or with matching placebo. After a Screening phase (Days -21 to -3) and Baseline (Days -2 and -1), eligible subjects were sequentially enrolled in 3 cohorts. Subjects within each cohort were randomized to vicriviroc or placebo in a ratio of 3:1 and administered study drug BID for 14 days, then followed for an additional 14 days. The next higher dose was not administered until the safety and tolerability of the preceding dose had been established, with not less than 7 days between each cohort. Subjects were confined at the study center from Day -2 through Day 7, and from Day 12 through Day 14 for safety, pharmacokinetic, and pharmacodynamic assessments. Outpatient visits were scheduled for Days 9, 11, 15, 16, 17, 21, 25, and 28. Blood samples for vicriviroc pharmacokinetics were drawn just before and up to 24 hours after the AM dose on Days 1 and 14. Trough samples were obtained just prior to the PM dose on Day 12 and prior to AM and PM doses on Day 13. In addition, samples were drawn on Days 16, 17, and 21. Viral pharmacodynamics for plasma HIV-I RNA at Screening, Days -1 through 7, Days 9 and 11, Days 13 through 17, and Days 21, 25, and 28 were evaluated using COBAS AMPLICOR™ HIV-I Test , vl.5 (Roche Diagnostics) with a COBAS AMPLICOR™ Analyzer to automate PCR amplification and detection. Fluorescence-activated cell sorting

(FACS) was used to assess total lymphocyte counts, presence of lymphocyte markers CD3 and CD3/CD4, as well as CCR5 and CXCR4 receptor densities associated with presence of CD3/CD4 and CD3/CD8, at Screening, and on Days -1, 2, 7, 14, and 28. ViroLogic, Inc. (now Monogram Biosciences, Inc.) determined phenotypic susceptibility of HIV-I isolates by using PhenoSense™ HIV test to analyze IC50/IC95. ViroLogic also employed the PhenoSense HIV Entry Tropism to determine co-receptor tropism (i.e., R5/X4 viral phenotype) by assaying chemokine co-receptor usage (CXCR4 and/or CCR5) at Screening and on Days -2, 7, 14, and 28. Physical examinations, vital signs, and clinical laboratory evaluations were conducted at Screening and at scheduled times during the study. Multiple time-matched 12-lead electrocardiograms (ECGs) were performed at Baseline (Day -1) and on Days 1, 7, and 14, and were over-read by a blinded third-party reviewer; in addition, single ECGs were performed at Screening and on Days 3, 5, 9, 11, 13, and 28. Subjects were continuously monitored for occurrences of adverse events (AEs).

Number of Subjects: Forty-nine subjects were enrolled; 48 subjects were treated; 47 subjects completed the study. Breakdown by treatment group was as follows: placebo, 13 subjects; vicriviroc 10 mg BID, 12 subjects; vicriviroc 25 mg BID, 13 subjects; and vicriviroc 50 mg BID, 11 subjects.

Diagnosis and Criteria for Inclusion: Adult males and females, aged 18 to 55 years, who were infected with a purely CCR5 -tropic HIV-I virus but had received no antiretroviral medication in the 8 weeks (or other drugs in the 2 weeks) prior to enrollment; and who had a CD4+ cell count ε200; HIV viral load between 5,000 and 200,000 copies/mL; and a body mass index (BMI) between 19 and 29 were eligible for study consideration. To qualify for this study, subjects had to be in otherwise good health based on medical history, including CNS history (i.e., lacking prior seizure disorder or head trauma); physical examination; ECG; and routine laboratory tests (blood chemistry, hematology, and urinalysis). Test Product, Dose, Mode of Administration: Vicriviroc (specifically, the maleate salt of Compound I).

• Group 1: 1 - 10-mg capsule orally BID on Days 1 to 13 and on Day 14 AM.

• Group 2: 1 • 25-mg capsule orally BID on Days 1 to 13 and on Day 14 AM. • Group 3: 2 • 25-mg capsules orally BID on Days 1 to 13 and on Day 14 AM.

Duration of Treatment: All subjects received their randomized treatment for 14 days with a 14-day follow-up period after the last dose.

Reference Therapy, Dose, Mode of Administration: Placebo matching vicriviroc.

• Group 1: 1 - 10-mg capsule orally BID on Days 1 to 13 and on Day 14 AM. • Group 2: 1 • 25-mg capsule orally BID on Days 1 to 13 and on Day 14 AM.

• Group 3: 2 • 25-mg capsules orally BID on Days 1 to 13 and on Day 14 AM. Pharmacokinetic Evaluation: Plasma vicriviroc concentration data were used to estimate the following pharmacokinetic parameters for Days 1 and 14: AUC(0-12 hr), Cmax, and Tmax. Pharmacokinetic parameters that were estimated only for Day 14 were: X¹A, CL/F, Vd/F, and R. Trough (Cmin) samples on Days 12 to 14 were used to assess the steady-state condition of vicriviroc.

Pharmacodynamic Evaluation: Pharmacodynamic variables included: HIV-I RNA viral load; FACS analysis of lymphocyte markers; R5/X4 viral phenotypes; susceptibility analysis. Safety Evaluation: Physical examinations, multiple time-matched ECGs, vital-signs assessments, and clinical laboratory tests were performed, and adverse events were recorded throughout the study.

Statistical Methods - Pharmacokinetic: A repeated-measures analysis of variance (ANOVA) model extracting subject, day, and dose as classificatory factors was used on the log-transformed Cmax and AUC values. A linear trend with dose was investigated, and a comparison of Day 1 AUC(0-12 hr) vs. Day 14 AUC(0-12 hr) was made. The dose normalized AUC(0-12 hr) and Cmax values for Day 14 were analyzed via a one-way ANOVA model. To assess steady state, an ANOVA was performed on the Cmin values for Days 12, 13, and 14 using subject and (successive) times as factors. Statistical Methods - Pharmacodynamic: Pharmacodynamic parameters were listed and summarized. In addition to parameters specified in the protocol, descriptive statistics including means, medians, and standard deviations were tabulated by treatment group for log 10 HIV-I RNA at baseline as well as for change from baseline in viral load at each time point.

Statistical Methods - Safety: All adverse events were listed and the data tabulated by treatment group. Adverse event tabulations included all treatment-emergent adverse events, which were further classified by severity and relationship to treatment. Clinically significant changes from Baseline in physical examinations were recorded as adverse events. The results of laboratory safety tests and vital signs measurements from all subjects were listed and reviewed. For ECG parameters, mean/median changes from Baseline were summarized by treatment group.

Demographics: A total of 49 subjects infected with HIV-I (40 male; 9 female) between the ages of 25 and 53 years were enrolled in this study. Overall, 43 subjects were Caucasian, 3 subjects were black, and 3 subjects were Hispanic. Median body mass index (BMI) was 23.40 (range, 16.6-33.2).

Pharmacokinetics: Mean pharmacokinetic parameters of vicriviroc are summarized in Table 3 below. Vicriviroc was rapidly absorbed with median peak plasma concentrations observed around (Tmax) 1.00 to 1.50 hours postdose. The intersubject variability was low to moderate; the CV ranged from 19% to 35% for Cmax and from 14% to 43% for AUC(0-12 hr). Dose-linear increases in Cmax and AUC(O- 12 hr) were observed as doses increased from 10 to 50 mg. A long terminal-phase half-life, ranging from 28.1 to 32.8 hours, was observed on Day 14. Steady state vicriviroc exposure was attained by Day 14 when given twice daily.

Pharmacodynamics: The median change from baseline in HIV-I RNA on Day 14 of treatment with vicriviroc for all three dose groups ranged from -0.96 to -1.47 loglO, with a significantly greater decrease in HIV-I RNA observed in the 25- and 50-mg dose groups as compared with the 10-mg group. Maximal group median values of viral suppression on treatment with vicriviroc ranged from 1.10 to 1.74 loglO.

Safety: No deaths were reported during the study. Sixty-nine percent of subjects reported at least 1 treatment emergent AE during the study: 62% of subjects who received placebo and 72% of subjects who received vicriviroc. There was no dose-related increase in the number of AEs reported with vicriviroc. The most commonly reported AEs with vicriviroc were headache (28%), abdominal pain (14%), nausea (14%), and pharyngitis (11%). Of these 4 AEs, only headache was reported with placebo (8%, 1 subject). Two subjects reported treatment-emergent serious adverse events (SAEs): one had influenza with three associated SAEs; another had second-stage syphilis which occurred 10 days after treatment ended. Mild, reversible elevations in liver function tests were observed in 4 subjects treated with vicriviroc. One subject treated with vicriviroc 50 mg BID had a solitary QTcF interval above the normal range during treatment.

Conclusion: • Vicriviroc doses of 10, 25, and 50 mg BID were well tolerated in these HIV-infected subjects. Most AEs were mild to moderate, and did not appear to be dose related. • Vicriviroc was rapidly absorbed and exhibited dose-linear pharmacokinetics with low intersubject variability and long terminal half-life in the dose range studied (10, 25, and 50 mg BID). • Potent viral suppression was observed in all three vicriviroc dose groups, based on the change from baseline in HIV-I RNA. Both 50 mg/day and 100 mg/day dose groups had a εl.5 loglO mean/median drop in viral load after dosing.

Clinical Study No. 2 Objectives: (i) To determine the multiple-dose pharmacokinetics of vicriviroc administered with low-dose ritonavir in healthy volunteers. (ii)To determine the multiple-dose safety and tolerance of vicriviroc when administered with low-dose ritonavir in healthy volunteers. Low-dose ritonavir was used to investigate pharmacokinetics of vicriviroc in healthy volunteers as the results are believed to be analogous to patients on an optimized background therapby regimen containing PI/r.

Methodology: This was a randomized (for first 2 cohorts) then sequential, open-label, rising-multiple-dose study designed to determine the pharmacokinetics and safety of vicriviroc when administered with ritonavir in healthy male and female subjects. A total of 48 subjects (12 subjects/cohort) were enrolled into 4 cohorts at a single study site. Volunteers were screened within 3 weeks of dosing, and eligible subjects were confined at the study center beginning approximately 36 hr before dosing began (evening of Day -2). The first 24 subjects enrolled were randomized in a 1:1 ratio to a vicriviroc (specifically, the maleate salt of Compound I) dose of either 20 mg once-a-day (QD) (Cohort 1) or 30 mg QD (Cohort 2) with ritonavir (100 mg QD). Vicriviroc was administered in the morning on Days 1-14 and ritonavir was administered in the morning on Days 1-20. Subjects remained at the study center for safety and pharmacokinetic assessments until all Day 18 procedures were completed, and returned to the clinic for outpatient visits on Days 19-21. Following review of safety and pharmacokinetic results from lower dose levels, 50 mg QD and 100 mg QD were chosen as the vicriviroc doses for Cohorts 3 and 4, respectively. Blood samples for determination of vicriviroc concentrations were obtained on Day 14 before dosing and at multiple postdose time points up to 24 hr after dosing; trough samples were also collected on Days 12 and 13. Additional blood samples for vicriviroc were collected daily on Days 15-21 (ie, 24 to 168 hr after the last vicriviroc dose). Blood samples for determination of ritonavir concentrations were obtained before dosing on Days 13-15. Blood samples for possible pharmacogenetic analyses were collected from all subjects on Day -2. The evaluation of safety included physical examinations, vital signs assessments, electrocardiograms (ECGs), and clinical laboratory tests conducted at Screening and at scheduled times during the study. The ECG evaluation included multiple time-matched ECGs on Days -1 and 14. Subjects were continuously observed and questioned throughout the study for possible occurrence of adverse events (AEs).

Criteria for Inclusion: Adult male and female subjects, aged 18 through 55 years, who had body mass-indices (BMI) between 19 and 32 were eligible for study consideration. To qualify for this study, subjects had to be in good health based on medical history, including a thorough CNS history (to exclude prior seizure disorder and/or head trauma); electroencephalogram (EEG); physical examination; ECG; and routine laboratory tests (blood chemistry, hematology and urinalysis).

Test Product, Dose, Mode of Administration: Vicriviroc (specifically, the maleate salt of Compound I) 10 mg tablets and/or 15 mg tablets were administered with ritonavir 100 mg capsules (Norvir®), orally, as follows: • Cohort 1: Vicriviroc 20 mg (2 x 10 mg tablets) QD for 14 days + ritonavir 100 mg QD for 20 days.

• Cohort 2: Vicriviroc 30 mg (2 x 15 mg tablets) QD for 14 days + ritonavir 100 mg QD for 20 days.

• Cohort 3: Vicriviroc 50 mg (5 x 10 mg tablets) QD for 14 days + ritonavir 100 mg QD for 20 days.

• Cohort 4: Vicriviroc 100 mg (6 x 15 mg tablets + 1 x 10 mg tablet) QD for 14 days + ritonavir 100 mg QD for 20 days.

Note: The vicriviroc doses for Cohorts 1 and 2 were determined at the outset of the study, and these cohorts were dosed simultaneously. The vicriviroc doses for Cohorts 3 and 4 were determined following review of safety and pharmacokinetic results from the previous lower dose levels, and Cohorts 3 and 4 were dosed sequentially.

Criteria for Evaluation: An analysis of the vicriviroc safety measurements and pharmacokinetic parameters were performed after completion of Cohorts 1 and 2, and then after completion of each subsequent cohort.

Pharmacokinetics: The following pharmacokinetic parameters were determined for vicriviroc after multiple doses (Day 14): maximum observed plasma concentration (Cmax), trough plasma concentration at predose (Cmin), time of Cmax (Tmax), and area under the plasma concentration-time curve from 0 to 24 hours (AUC[0-24 hr]). Additionally, when the data permitted, the apparent total body clearance (CL/F), the apparent volume of distribution (Vd/F), and the terminal phase half-life (tVa) were also to be calculated. Steady state for vicriviroc was assessed using trough concentration samples obtained on Days 12 to 15. Ritonavir concentrations were determined for samples taken on Days 13 to 15.

Safety: Physical examinations, ECGs, and clinical laboratory tests were performed; vital signs were monitored; and AEs were recorded. The ECG evaluation included multiple time-matched ECGs on Days -1 and 14.

Statistical Methods for Pharmacokinetics: The primary pharmacokinetic parameters for vicriviroc are AUC and Cmax. Point estimates along with 90% CIs were provided for each cohort based on log-transformed AUC and Cmax. Steady state was characterized for each dose using the trough concentrations from Days 12 to 15. Analysis of pharmacokinetic parameters was performed after completion of Cohorts 1 and 2, and then after completion of each subsequent cohort. Summary statistics (eg, means and standard deviations) were provided for the vicriviroc pharmacokinetic parameters and the concentration data at each sample time.

Statistical Methods for Safety: All AEs reported during the study were listed by subject and body system. Tabulations of AEs included all treatment-emergent AEs (TEAEs) and treatment-related TEAEs, which were classified by body system and dose-level cohort. Data from hematology and blood chemistry tests, vital signs assessments, and ECGs were listed and reviewed for each subject, and clinically significant findings were recorded as AEs. Laboratory values outside the laboratory's reference ranges were flagged. The results of physical examinations were reviewed and clinically significant changes from Screening were recorded as AEs. The ECG parameters as well as the safety laboratory variables and vitals signs measurements were summarized using descriptive statistics.

Demographic and Baseline Characteristics: A total of 48 (31 male and 17 female) healthy subjects between the ages of 18 and 54 years (range of mean age among cohorts: 37.7- 41.4 years) were randomized to treatment. The majority of subjects in each cohort were white: range of 67% to 83% among cohorts. Treatment groups were similar with respect to demographic characteristics.

Pharmacokinetics: Summary statistics (mean and %CV) for the vicriviroc pharmacokinetic parameters on Day 14 are provided for each treatment group in Table 4 below.

Safety: A total of 16 subjects (33%) reported at least 1 TEAE during the study: 6 (50%) subjects dosed with vicriviroc 20 mg + ritonavir 100 mg (Cohort 1); 5 (42%) subjects dosed with vicriviroc 30 mg + ritonavir 100 mg (Cohort 2); 1 (8%) subject dosed with vicriviroc 50 mg + ritonavir 100 mg (Cohort 3); and 4 (33%) subjects dosed with vicriviroc 100 mg + ritonavir 100 mg (Cohort 4). There were no apparent dose-related trends in occurrence of TEAEs.

Gastrointestinal (GI) TEAEs were the most common events, reported by 5 (42%) subjects, 4 (33%) subjects, 1 (8%) subject, and 1 (8%) subject in Cohorts 1-4, respectively. Of the GI TEAEs, diarrhea and constipation were the most frequently reported. Although the majority of TEAEs were considered by the investigator to be possibly related to study treatment, all TEAEs reported during the study were rated as mild in severity and no subject required medication for treatment of a TEAE. There were no serious AEs (SAEs), and no subjects were withdrawn from treatment because of TEAEs. No clinically significant changes in blood chemistry or hematological parameters, vital signs, or ECGs results were reported. Results of the multiple time-matched ECGs conducted at Baseline (Day -1) and on Day 14 indicated that no subject had an increase >30 msec in QTc interval with the Fridericia correction (QTcF interval) from the time-matched Baseline. All values for QTcF intervals measured on Day 14 remained within the gender specific normal ranges, i.e., <430 msec for male subjects and <450 msec for female subjects. Conclusions:

• Cmax, Cmin and AUC(0-24 hr) of vicriviroc increased with increases in dose (20 mg, 30 mg, 50 mg and 100 mg) when administered once a day with 100 mg ritonavir. Similar CL/F values suggested no change in elimination across doses. Steady state was attained by Day 14.

• Vicriviroc at once-daily doses of 20 mg, 30 mg, 50 mg, and 100 mg administered for 2 weeks along with ritonavir (100 mg QD) to healthy subjects was safe and well tolerated. There were no apparent dose-related trends in occurrence of TEAEs. No clinically significant changes in blood chemistry or hematological parameters, vital signs, or ECGs results were reported.

Clinical Study No. 3 Objectives: (i) To evaluate the effect of a protease inhibitor (e.g., darunavir) on the pharmacokinetics of vicriviroc in the presence of ritonavir; and (ii) To evaluate the safety and tolerance of vicriviroc with concomitant administration of PI/r (darunavir and ritonavir). Methodology: This was an open-label, fixed-sequence, two-period, multiple-drug interaction study conducted at a single study center in 12 healthy adult subjects. The study was conducted in conformance with Good Clinical Practice (GCP). Volunteers were screened within 3 weeks of dosing, and eligible subjects were confined at the study center beginning 12 hr before dosing started (Day -1) for baseline assessments to reconfirm eligibility. Subjects received their first dose of study drugs at approximately 8 AM on Day 1. For the first 14 days of treatment (Days 1-14), subjects received vicriviroc (specifically, the maleate salt of Compound I) (30 mg once-a-day in the morning (QAM)) in combination with ritonavir (100 mg BID). For the following 14 days (Days 15-28), darunavir (600 mg BID) was added to the existing treatment regimen. All study drugs were taken with food. Subjects remained at the study center through Day 29 for safety and pharmacokinetic assessments, and returned for a follow-up visit on Day 33. Serial blood samples for pharmacokinetic analysis of vicriviroc were obtained on Days 14 and 28 starting before dosing through 24 hr after dosing; trough samples were also collected on Days 12, 13, 26, and 27. Blood samples for analysis of ritonavir were collected before the morning dose on Days 14 and 28. Serial blood samples for analysis of darunavir were obtained on Day 28 starting before dosing through 24 hr after dosing. Blood samples for possible pharmacogenetic analyses were also collected from consenting subjects on Day -1. The evaluation of safety included physical examinations, vital signs assessments, electrocardiograms (ECGs), and clinical laboratory tests conducted at Screening and at scheduled times during the study. Subjects were continuously observed and questioned throughout the study for possible occurrence of adverse events (AEs). Number of Subjects: Twelve subjects were enrolled and all subjects completed the study. Diagnosis and Criteria for Inclusion: Adult male and female subjects, aged 18 through 55 years, who had body mass indices (BMI) between 19 and 32 kg/m² were eligible for study consideration. To qualify for this study, subjects had to be in good health based on medical history, including a thorough CNS history (to exclude prior seizure disorder and/or head trauma); physical examination; ECG; and routine laboratory tests (blood chemistry, hematology and urinalysis).

Test Therapy, Dose, Mode of Administration: Vicriviroc (specifically, the maleate salt of Compound I) 30 mg tablet QAM x 28 days (Days 1 to 28), ritonavir (Norvir®) 100 mg capsule BID x 28 days (Days 1 to 28), and darunavir (Prezista™) 600 mg (2 x 300 mg tablets) BID x 14 days (Days 15 to 28). All medications were given orally with food.

Reference Therapy, Dose, Mode of Administration: Vicriviroc (specifically, the maleate salt of Compound I) 30 mg tablet QAM x 14 days and ritonavir (Norvir®) 100 mg capsule BID x 14 days (Days 1 to 14). All medications were given orally with food. Duration of Treatment: Vicriviroc QD and ritonavir BID were administered for 28 days (Days 1 to 28), and darunavir BID was administered for 14 days (Days 15 to 28).

Criteria for Evaluation - Pharmacokinetics: The following pharmacokinetic parameters were determined for vicriviroc and darunavir after multiple doses: Cmax, trough plasma concentration at predose (0 hr) (Cmin), time of observed maximum Day 28 (AUC[0-24 hr] for vicriviroc and AUC[0-12 hr] for darunavir). Additionally, apparent total body clearance (CL/F) was calculated. Ritonavir plasma concentration at time 0 hr (Cp 0-hr) was determined on Day 14 and Day 28.

Criteria for Evaluation -Safety: Physical examinations, ECGs, and clinical laboratory tests were performed; vital signs were monitored; and AEs were recorded. Statistical Methods - Pharmacokinetics: Summary statistics (means, standard deviations [SDs] and coefficients of variation [CVs]) for the concentration data at each sampling time and the pharmacokinetic parameters on Days 14 and 28 were provided. The log- transformed data for vicriviroc AUC, Cmax, and Cmin on Days 14 and 28 were statistically analyzed using a one-way analysis of variance (ANOVA) model extracting the effects due to treatment and subject. The primary comparisons of interest were the contrasts between vicriviroc Cmax and AUC on Day 28 (vicriviroc + ritonavir + darunavir) vs. vicriviroc Cmax and AUC, respectively, on Day 14 (vicriviroc + ritonavir). The relative bioavailability for Day 28 vs. Day 14 was provided for the log-transformed AUC, Cmax, and Cmin along with the associated 90% confidence intervals (CIs). Steady state for plasma vicriviroc concentration during the first treatment period (vicriviroc + ritonavir) was evaluated using the trough values sampled on Days 12-15, and during the second treatment period (vicriviroc + ritonavir + darunavir) using the trough values sampled on Days 26-29.

Statistical Methods - Safety: All AEs noted during the study were listed. The AEs were tabulated by treatment and body system/organ class (BSOC). Data from hematology and blood chemistry tests, vital signs assessments, and ECGs were listed and reviewed for each subject, and clinically significant findings were recorded as AEs. Laboratory values outside the laboratory's reference ranges were flagged. The results of physical examinations were reviewed and clinically significant changes from Screening were recorded as AEs.

Demographic and Baseline Characteristics: A total of 12 (6 male and 6 female) healthy subjects between the ages of 21 and 53 years (mean, 42.3 years) were enrolled in the study. Ten (83%) of the subjects were white, and 2 (17%) subjects were black or African American; all subjects were of Hispanic or Latino ethnicity.

Clinical Pharmacology - Pharmacokinetics: Vicriviroc exposure when vicriviroc was coadministered with ritonavir and darunavir was similar to the exposure when vicriviroc was coadministered with ritonavir alone, indicating no substantive interaction between vicriviroc and darunavir in a ritonavir-containing regimen. Plasma concentrations of vicriviroc, in the presence of ritonavir, were consistent for the samples collected on Days 12 through 15. Plasma concentrations of vicriviroc, in the presence of PI/r (i.e., ritonavir and darunavir), were consistent for the samples collected on Days 26 through 29. The mean treatment ratios and the 90% CIs for AUC(0-24 hr), Cmax, and Cmin of vicriviroc in the presence of ritonavir, with and without darunavir, are presented in the following Table 5:

The pharmacokinetic parameters of vicriviroc coadministered with ritonavir in the presence or absence of darunavir are summarized in Table 6 below.

Safety: A total of 7 (58%) subjects reported at least one treatment-emergent AE (TEAE) during the study. Three (25%) subjects reported a TEAE that began while the subjects were receiving vicriviroc with ritonavir alone; 5 (42%) subjects reported one or more TEAEs that began after darunavir was added to the treatment regimen. The only TEAEs that were reported while subjects were receiving vicriviroc with ritonavir alone were diarrhea, constipation, and headache, in one subject each. The TEAEs that occurred in more than one subject during the study were diarrhea (3 subjects), constipation (2 subjects), and increased alanine aminotransferase (ALT; 2 subjects). Gastrointestinal disorders were the most common type of TEAE overall, reported in 5 (42%) subjects. Conclusions:

• The pharmacokinetic parameters of vicriviroc were not substantially altered in the PI/r regimen with darunavir and ritonavir. Consequently, the dose of vicriviroc does not have to be adjusted in such a regimen.

• Vicriviroc (30 mg QD) when administered with ritonavir (100 mg BID) alone or with the addition of darunavir (600 mg BID) was safe and well tolerated in healthy adult subjects.

Claims

1. A tablet for oral administration comprising a granulate comprising Compound I or a pharmaceutically acceptable salt thereof and a binder, a disintegrant, and a diluent, wherein Compound I or a pharmaceutically acceptable salt thereof comprises 10% to 20% by weight of the tablet.

2. The tablet of Claim 1 wherein the pharmaceutically acceptable salt of Compound I is a maleate salt at a 30 mg dose.

3. The tablet of Claim 1 wherein the binder is microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural gum, synthetic gum, povidone (PVP), pregelatinized starch, HPC, HPMC, or a combination of two or more thereof.

4. The tablet of Claim 1 wherein the binder is PVP.

5. The tablet of Claim 1 wherein the disintegrant is sodium starch glycolate, carboxymethylcellulose or a salt thereof, croscarmellose or a salt thereof, crospovidone or a salt thereof, methylcellulose, microcrystalline cellulose, one- to six-carbon alkyl-substituted HPC, starch, pregelatinized starch, sodium alginate, or a combination of two or more thereof.

6. The tablet of Claim 1 wherein the disintegrant is a croscarmellose salt.

7. The tablet of Claim 1 wherein the diluent is lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, dibasic calcium phosphate dehydrate, or a combination of two or more thereof.

8. The tablet of Claim 1 wherein the diluent is microcrystalline cellulose.

9. The tablet of Claim 1 wherein the diluent is a combination of microcrystalline cellulose and lactose monohydrate.

10. The tablet of Claim 1 further comprising an extragranular excipient which is lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, dibasic calcium phosphate dehydrate, or a combination of two or more thereof.

11. The tablet of Claim 1 further an extragranular excipient which is microcrystalline cellulose.

12. The tablet of Claim 1 further comprising an extragranular excipient which is sodium starch glycolate, carboxymethylcellulose or a salt thereof, croscarmellose or a salt thereof, crospovidone or a salt thereof, methylcellulose, microcrystalline cellulose, one- to six-carbon alkyl-substituted HPC, starch, pregelatinized starch, sodium alginate, or a combination of two or more thereof.

13. The tablet of Claim 1 further comprising an extragranular excipient which is a croscarmellose salt.

14. The tablet of Claim 1 further comprising an extragranular excipient which is magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, sodium lauryl sulfate, or a combination of two or more thereof.

15. The tablet of Claim 1 further comprising an extragranular excipient which is magnesium stearate.

16. The tablet of Claim 1 wherein Compound I or a pharmaceutically acceptable salt thereof comprises 20% by weight of the tablet.

17. The tablet of Claim 1 wherein the granulate comprises 65% to 70% by weight of the tablet.

18. The tablet of Claim 1 wherein the binder comprises 2% to 8% by weight of the tablet.

19. A tablet comprising a granulate of Compound I or a pharmaceutically acceptable salt thereof which provides a mean steady-state AUC of Compound I that is at least 4968 ng-hr/ml when administered at a dose equivalent to 24.6 mg free base of Compound I once-a-day to a patient on an optimized background therapy regimen containing PI/r.

20. The tablet of Claim 19 which provides a mean steady-state Cmax of Compound I that is at least 297 ng/ml at a mean Tmax that is in the range from about 1 hour to about 3 hours.

21. A tablet comprising a granulate of Compound I or a pharmaceutically acceptable salt thereof which provides a mean steady-state Cmin of Compound I that is at least 200 ng/ml when administered at a dose equivalent to 24.6 mg free base of Compound I once-a-day to a patient on an optimized background therapy regimen containing PI/r.

22. The tablet of Claim 21 wherein the pharmaceutically acceptable salt of Compound I is a maleate salt at a 30 mg dose.

23. The tablet of Claim 21 wherein the granulate further comprises a binder, a disintegrant, and a diluent.

24. The tablet of Claim 1 wherein the granulate is prepared by a process comprising:

(a) dry-blending:

(i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) a disintegrant, and a diluent to provide a first dry-blended powder;

(b) agglomerating the first dry-blended powder prepared in Step "a" in a high shear granulator using a granulating solution comprising water and a binder;

(c) forming a wet milled granulate by wet-milling the agglomerate prepared in Step "b";

(d) forming a dried granulate by drying the wet milled granulate from Step "c"; and

(e) dry-milling the dried granulate from Step "d".

25. A method for treating HIV infection in a patient on an optimized background therapy regimen containing PI/r comprising administering to the patient in need thereof a therapeutically effective amount of the tablet of any one of Claims 1, 19, or 21.

26. A method for treating an inflammatory disease comprising administering to a patient in need thereof a therapeutically effective amount of the tablet of Claim 1.