HIV-1 Coreceptor Usage Assessment by Ultra-Deep Pyrosequencing and Response to Maraviroc.

BACKGROUND: Maraviroc is an HIV entry inhibitor that alters the conformation of CCR5 and is poorly efficient in patients infected by viruses that use CXCR4 as an entry coreceptor. The goal of this study was to assess the capacity of ultra-deep pyrosequencing (UDPS) and different data analysis approaches to characterize HIV tropism at baseline and predict the therapeutic outcome on maraviroc treatment. METHODS: 113 patients with detectable HIV-1 RNA on HAART were treated with maraviroc. The virological response was assessed at months 1, 3 and 6. The sequence of the HIV V3 loop was determined at baseline and prediction of maraviroc response by different software and interpretation algorithms was analyzed. RESULTS: UDPS followed by analysis with the Pyrotrop software or geno2pheno algorithm provided better prediction of the response to maraviroc than Sanger sequencing. We also found that the H34Y/S substitution in the V3 loop was the strongest individual predictor of maraviroc response, stronger than substitutions at positions 11 or 25 classically used in interpretation algorithms. CONCLUSIONS: UDPS is a powerful tool that can be used with confidence to predict maraviroc response in HIV-1-infected patients. Improvement of the predictive value of interpretation algorithms is possible and our results suggest that adding the H34S/Y substitution would substantially improve the performance of the 11/25/charge rule.

The utility of genotypic tropism testing in clinical practice.

A review of a large number of HIV-1 tropism test requests (n = 1148) performed at a London tertiary referral centre was carried out. The aim was to establish whether these were being performed in line with recommendations from published guidelines and whether this represented the most cost-effective use of these tests in informing prescribing decisions of the CCR5 antagonist drug, maraviroc. The cost of these assays within the UK was covered by commercial funding until April 2013 which has subsequently been withdrawn. Furthermore, all healthcare settings are under increasing cost constraints and hence establishing the real utility and appropriate use of these tests is of vital importance.

Results of external quality assessment for proviral DNA testing of HIV tropism in the Maraviroc Switch collaborative study.

The Maraviroc Switch collaborative study (MARCH) is a study in aviremic patients on stable antiretroviral therapy and utilizes population-based sequencing of proviral DNA to determine HIV tropism and susceptibility to maraviroc. An external quality assessment (EQA) program was implemented to ensure competency in assessing the tropism of clinical samples conducted by MARCH laboratories (n = 14). The MARCH EQA has three prestudy phases assessing V3 loop sequencing and tropism determination using the bioinformatic algorithm geno2pheno, which generates a false-positive rate (FPR). DNA sequences with low FPRs are more likely to be from CXCR4-using (X4) viruses. Phase 1 of the EQA involved chromatogram interpretation. Phases 2, 2/3, and 3 involved patient and clonal samples. Clinical samples used in these phases were from treatment-experienced HIV-infected volunteers; 18/20 had viral loads of <50 copies/ml, and 10/15 were CXCR4-tropic on prior phenotyping. All samples were tested in triplicate, and any replicate with a geno2pheno FPR of <10% was designated X4. Performance was deemed adequate if ≤2 R5 and ≤1 X4 specimens were miscalled. For several clinical samples in the EQA, triplicate testing revealed marked DNA variability (FPR range, 0 to 96.7%). Therefore, a consensus-based approach was employed for each sample, i.e., a median FPR across laboratories was used to define sample tropism. Further sequencing analysis showed mixed viral populations in the clinical samples, explaining the differences in tropism predictions. All laboratories passed the EQA after achieving predefined competence thresholds in either of the phase 2 rounds. The use of clinical samples from patients resembling those who were likely to be screened in the MARCH, coupled with triplicate testing, revealed inherent DNA variability that might have been missed if single or duplicate testing and/or clonal samples alone were used. These data highlight the importance of intensive EQA of tropism laboratories before embarking on clinical studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01384682 [http://www.clinicaltrials.gov/ct2/show/study/NCT01384682?term=NCT01384682&rank=1].).

Cost-effectiveness of maraviroc for antiretroviral treatment-experienced HIV-infected individuals in Mexico.

OBJECTIVE: Maraviroc is the first approved drug in a new class of antiretrovirals, the CCR5 antagonists. The objective of this study was to predict the long-term clinical impact and cost-effectiveness of maraviroc in treatment-experienced adults with HIV/AIDS in Mexico. METHODS: The AntiRetroviral Analysis by Monte Carlo Individual Simulation (ARAMIS) model was adapted to the Mexican context to predict clinical and economic outcomes of treating with optimized background therapy (OBT) versus testing for viral tropism status and treating with OBT ± maraviroc accordingly in treatment-experienced adults in Mexico. Baseline characteristics and efficacy were from the MOTIVATE trials' screening cohort. Costs and population mortality data were specific to Mexico. Results were reported from the perspective of health care payers in 2008 Mexican pesos (converted to 2008 US$ in parentheses). RESULTS: Compared to treatment with OBT alone, treatment with OBT ± maraviroc contingent on tropism test result increased projected undiscounted life expectancy and discounted quality-adjusted life expectancy from 7.54 to 8.71 years and 4.42 to 4.92 quality-adjusted life years (QALYs), respectively, at an incremental cost of $228,215 (US$21,329). The resultant incremental cost-effectiveness ratio (ICER) was $453,978 (US$42,429) per QALY gained. The ICER was somewhat lower when maraviroc was modeled in individuals susceptible to ≤ 2 components of OBT ($407,329; US$38,069), while the ICER was higher in individuals susceptible to ≥3 OBT components ($718,718; US$67,171). CONCLUSION: In treatment-experienced individuals with HIV/AIDS in Mexico, maraviroc may be cost-effective, particularly in individuals with limited options for active antiretroviral therapy (ART).

A microsimulation of the cost-effectiveness of maraviroc for antiretroviral treatment-experienced HIV-infected individuals.

PURPOSE: Maraviroc (MVC) is the first approved CCR5 antagonist. The aim of this study was to explore the cost-effectiveness of MVC in treatment-experienced or treatment-resistant HIV-infected adults. METHODS: The validated HIV microsimulation model ARAMIS was used to predict clinical and economic outcomes of treating patients with optimized background therapy (OBT) alone, as compared to a strategy of testing for the patient's viral tropism and treating with OBT with or without (+/-) MVC in a cohort corresponding to the MOTIVATE screening cohort. RESULTS: Compared to treatment with OBT alone, a treatment strategy of OBT +/- MVC (twice daily) according to tropism test result was predicted to increase CD4+ cell count after 5 years (from mean 249 to 360 cells/microL), undiscounted life expectancy (7.6 to 8.9 years), and quality-adjusted life years (QALYs; from 4.99 to 5.71) for an additional $40,500, giving an incremental cost-effectiveness ratio of $56,400 per QALY gained. The result was relatively insensitive to alternative clinical and cost assumptions within reasonable ranges, but for individuals with HIV susceptible to only two or fewer components of OBT, the ICER decreased to $52,000 per QALY gained. CONCLUSION: MVC is cost-effective, especially among individuals with few remaining options for active antiretroviral therapy.

Maraviroc: a review of its use in the management of CCR5-tropic HIV-1 infection.

Maraviroc (Celsentri; Selzentry) is a CCR5 coreceptor antagonist used in the treatment of CCR5-tropic HIV-1 infection. Administered orally twice daily, maraviroc, in combination with optimized background therapy regimens, showed good virological and immunological efficacy over 48 weeks in antiretroviral treatment-experienced patients aged > or = 16 years with CCR5-tropic HIV-1 infection, in the randomized, double-blind, placebo-controlled, multicentre, MOTIVATE 1 and MOTIVATE 2 studies. Initial data indicate that the efficacy of maraviroc in this patient population is sustained for up to 96 weeks. In the MERIT study in antiretroviral therapy-naive patients aged > or = 16 years with CCR5-tropic HIV-1 infection, maraviroc was noninferior to efavirenz (each in combination with zidovudine/lamivudine) for one primary virological endpoint (HIV-1-RNA levels < 400 copies/mL), but not for the other primary endpoint (HIV-1 RNA levels < 50 copies/mL) in the primary analysis at 48 weeks. However, in a subsequent analysis, which used a more sensitive tropism testing assay than the one originally used and retrospectively excluded patients with non CCR5-tropic HIV-1 infection who were ineligible for inclusion in the study, maraviroc demonstrated noninferiority to efavirenz on both primary virological endpoints. Maraviroc showed sustained virological efficacy in this patient population and improved immunological markers for up to 96 weeks. Maraviroc was generally well tolerated by both treatment-experienced and treatment-naive patients with CCR5-tropic HIV-1 infection. Thus, maraviroc, as a component of antiretroviral combination therapy regimens, is an important option for use in treatment-experienced adults with CCR5-tropic HIV-1 infection. Available data indicate that maraviroc may also have a role in treatment-naive adults with CCR5-tropic HIV-1 infection, a population in whom CCR5-tropic HIV-1 is often the major quasispecies.

Assessment of the pharmacokinetics of co-administered maraviroc and raltegravir.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Maraviroc is a CCR5 receptor antagonist, while raltegravir is a HIV-1 integrase inhibitor. * Based on the known metabolic pathways (CYP3A4 for maraviroc and UGT1A1 for raltegravir), interaction between the two drugs is unlikely. However, unexpected interactions have been reported for other antiretroviral drugs. * As both these drugs are likely to be used in combination, this study evaluated the pharmacokinetic interaction between them. WHAT THIS STUDY ADDS: * Relative to individual monotherapy, co-administration resulted in a 20% and 33% decrease in mean C(max), and 14% and 37% decrease in mean AUC of maraviroc and raltegravir, respectively. * Co-administration was generally safe and well tolerated in healthy subjects. * These changes are not likely to be clinically relevant, thus no dose adjustment is necessary. AIMS: To assess the two-way pharmacokinetic interaction between maraviroc and raltegravir. METHODS: In this open-label, multiple-dose, fixed-sequence study, 18 healthy, human immunodeficiency virus (HIV)-seronegative subjects received the following: days 1-3 raltegravir 400 mg q12h, days 4-5 washout, days 6-11 maraviroc 300 mg q12h, and days 12-14 raltegravir 400 mg q12h + maraviroc 300 mg q12h. Serial 12-h blood samples were collected on days 3 (raltegravir), 11 (maraviroc) and 14 (raltegravir + maraviroc). Plasma samples were assayed by validated liquid chromatography tandem mass spectrometry assays. Test/reference ratios and 95% confidence intervals (CIs) were determined for pharmacokinetic parameters. RESULTS: For maraviroc, the test/reference % ratio (95% CI) for AUC(tau) was 85.8 (78.7, 93.5), for C(max) was 79.5 (64.8, 97.5) and for C(min) was 90.3 (84.2, 96.9). For raltegravir, the test/reference % ratio (95% CI) for AUC(tau) was 63.3 (41.0, 97.6), for C(max) was 66.8 (37.1, 120.0) and for C(min) was 72.4 (55.1, 95.2). In all subjects, maraviroc average concentrations (AUC(tau) divided by 12) were >100 ng ml(-1), the threshold value below which there is an increased risk of virological failure. Based on clinical experience for raltegravir, mean C(min) decreases >60% are considered to be clinically relevant for short-term activity; however, in the present study mean changes were only 28% and thus not considered to be of clinical relevance. CONCLUSIONS: Co-administration of maraviroc and raltegravir decreased systemic exposure of both drugs; however, these are not likely to be clinically relevant. Safety and efficacy studies may help in understanding the role of this combination in the treatment of HIV infection.

Cost-effectiveness of optimized background therapy plus maraviroc for previously treated patients with R5 HIV-1 infection from the perspective of the Spanish health care system.

OBJECTIVE: The aim of this work was to evaluate the cost-effectiveness, from the perspective of the Spanish health care system, of optimized background therapy (OBT) plus maraviroc 300 mg BID versus OBT plus placebo in previously treated patients with R5 HIV-1 infection. METHODS: A lifetime cohort model was developed, based on 24- and 48-week pooled results from the Maraviroc Versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) studies 1 and 2, to reflect the Spanish health care system's perspective. Treatment duration was based on clinical trial follow-up from MOTIVATE 1 and 2. Clinical data, cohort characteristics, success probability, CD4 increase rate, CD4 cell status link to disease states, and adverse-event probability were taken from the MOTIVATE trials and other published literature. Other input parameters were taken from published sources. Antiretroviral (ARV) costs were derived from local sources. Non-ARV drug costs were obtained from published literature and a cost database. All costs were calculated as year-2009 euros. The annual discount rate was set at 3.0%. The main outcomes were cost per life-year gained (LYG) and cost per quality-adjusted life-year (QALY) gained. Uncertainty was assessed with one-way and probabilistic sensitivity analyses. RESULTS: In the model analysis, adding maraviroc to OBT was associated with an increase of 0.952 LYG and 0.909 QALY. Total costs were €275,970 for maraviroc plus OBT and €254,655 for placebo plus OBT (difference: €21,315). The incremental cost per LYG was €22,398 and the incremental cost per QALY gained was €23,457. The model appeared to be robust for variations in key parameters. Results from the probabilistic sensitivity analyses indicated that the probability of the cost per QALY being below €30,000 was 99%. CONCLUSION: Despite the limitations of the model, our analysis suggested that OBT plus maraviroc 300 mg BID is a clinically valuable option, and cost-effective from the perspective of the Spanish health care system, for previously treated patients with R5 HIV-1 infection.

Preclinical assessment of the distribution of maraviroc to potential human immunodeficiency virus (HIV) sanctuary sites in the central nervous system (CNS) and gut-associated lymphoid tissue (GALT).

1. Growing knowledge of the pathogenesis of human immunodeficiency virus (HIV)-1 infection has led to the identification of potential virus sanctuary sites within the central nervous system and gut-associated lymphoid tissue. 2. Maraviroc is a novel CCR5 antagonist for the treatment of HIV-1 infection. Disposition studies have been performed within the preclinical testing of maraviroc to determine its distribution to these anatomical sites. 3. Maraviroc, which is a substrate of the efflux transporter P-glycoprotein, shows limited distribution to the central nervous system as evidenced by cerebrospinal fluid concentrations that were 10% of the free plasma concentration following intravenous infusion to rats. Tissue distribution studies also indicated limited distribution of radioactivity into brain tissue of rats. 4. Radioactivity in gut-associated lymphoid tissue lymph nodes exceeded the concentrations in blood and concentrations in the contents of thoracic ducts of the lymphatic system were similar to blood levels following intravenous administration to rats.

Maraviroc: a CCR5-receptor antagonist for the treatment of HIV-1 infection.

BACKGROUND: The emergence of viral resistance is one of the greatest challenges in the treatment of HIV infection. Maraviroc is the first member of a new class of antiretroviral medications, the CCR5-receptor antagonists. It is approved by the US Food and Drug Administration (FDA) for use in combination with other antiretroviral agents in treatment-experienced patients infected with multidrug-resistant, CCR5-tropic HIV-1. OBJECTIVE: This article provides an overview of the pharmacology, efficacy, and tolerability of maraviroc in the treatment of HIV-1 infection. METHODS: Relevant information was identified through a search of MEDLINE (January 2000-May 2008) using the terms maraviroc, UK-427,857, and CCR5-receptor antagonist. Also consulted were abstracts from the International AIDS Society Conference, the Conference on Retroviruses and Opportunistic Infections, and other relevant scientific meetings. Additional publications were found by searching the reference lists of the identified articles and the FDA Web site. RESULTS: Maraviroc is a selective, reversible, small-molecule CCR5-receptor antagonist. In vitro, it has potent anti-HIV-1 activity, with a mean 90% inhibitory concentration of 2.0 nmol/L. It is widely distributed, with a V(d) of approximately 194 L. Maraviroc is moderately metabolized in the liver (65.3%), primarily via the cytochrome P450 3A4 isozyme. It has an elimination t(1/2) of 15.9 to 22.9 hours. Until more data are available, maraviroc should be avoided in patients with severe hepatic insufficiency; dose adjustment does not appear to be necessary on the basis of age, sex, or renal function. In 2 Phase IIb/III studies, maraviroc 300 mg PO QD or BID was found to be more efficacious than placebo in reducing the viral load at 48 weeks in treatment-experienced, CCR5-tropic HIV-1-infected patients receiving an optimized background regimen (difference vs placebo-QD arm: -0.89 log(10) copies/mL [97.5% CI, -1.17 to -0.62]; BID arm: -1.05 log(10) copies/mL [97.5% CI, -1.33 to -0.78]). The proportion of patients with a viral load < 50 copies/mL was 43.2% in the QD arm and 45.5% in the BID arm, compared with 16.7% in the placebo arm (P < 0.001, both treatment arms vs placebo). In treatment-naive patients infected with CCR5-tropic virus only, maraviroc 300 mg PO BID was not noninferior to oral efavirenz 600 mg QD (difference = -4.2%; lower bound of the 1-sided 97.5% CI, -10.9 [predefined statistical cutoff for noninferiority, -10]). Maraviroc was generally well tolerated in clinical trials. The most frequently reported (> or = 5%) adverse events were upper respiratory tract infection (20.0%), cough (12.7%), pyrexia (12.0%), rash (9.6%), musculoskeletal complaints (8.7%), gastrointestinal and abdominal pain (8.2%), dizziness (8.2%), appetite disorders (7.3%), insomnia (7.0%), herpes infection (6.8%), sinusitis (6.3%), joint complaints (6.1%), bronchitis (5.9%), and constipation (5.4%). The recommended dose of maraviroc differs based on concomitant medications, ranging from 150 to 600 mg BID. CONCLUSION: When used in combination with other antiretroviral agents, maraviroc appears to be a promising agent for treatment-experienced patients infected with multidrug-resistant, CCR5-tropic HIV-1.

Maraviroc: in vitro assessment of drug-drug interaction potential.

AIMS: To characterize the cytochrome P450 enzyme(s) responsible for the N-dealkylation of maraviroc in vitro, and predict the extent of clinical drug-drug interactions (DDIs). METHODS: Human liver and recombinant CYP microsomes were used to identify the CYP enzyme responsible for maraviroc N-dealkylation. Studies comprised enzyme kinetics and evaluation of the effects of specific CYP inhibitors. In vitro data were then used as inputs for simulation of DDIs with ketoconazole, ritonavir, saquinavir and atazanvir, using the Simcyptrade mark population-based absorption, distribution, metabolism and elimination (ADME) simulator. Study designs for simulations mirrored those actually used in the clinic. RESULTS: Maraviroc was metabolized to its N-dealkylated product via a single CYP enzyme characterized by a K(m) of 21 microM and V(max) of 0.45 pmol pmol(-1) min(-1) in human liver microsomes and was inhibited by ketoconazole (CYP3A4 inhibitor). In a panel of recombinant CYP enzymes, CYP3A4 was identified as the major CYP responsible for maraviroc metabolism. Using recombinant CYP3A4, N-dealkylation was characterized by a K(m) of 13 microM and a V(max) of 3 pmol pmol(-1) CYP min(-1). Simulations therefore focused on the effect of CYP3A4 inhibitors on maraviroc pharmacokinetics. The simulated median AUC ratios were in good agreement with observed clinical changes (within twofold in all cases), although, in general, there was a trend for overprediction in the magnitude of the DDI. CONCLUSION: Maraviroc is a substrate for CYP3A4, and exposure will therefore be modulated by CYP3A4 inhibitors. Simcyptrade mark has successfully simulated the extent of clinical interactions with CYP3A4 inhibitors, further validating this software as a good predictor of CYP-based DDIs.

Assessment of the pharmacokinetics, safety and tolerability of maraviroc, a novel CCR5 antagonist, in healthy volunteers.

AIMS: To evaluate the pharmacokinetics, safety and tolerability of single and multiple oral doses of maraviroc in healthy volunteers. METHODS: Three double-blind, placebo-controlled, dose-escalation studies with either single or multiple doses of maraviroc were conducted in healthy volunteers. Plasma and urine samples were collected to investigate the pharmacokinetics of maraviroc and evaluate any changes with respect to dose and duration/frequency of dosing. Safety and toleration of maraviroc were also assessed. RESULTS: Maraviroc is rapidly absorbed following oral administration, and plasma T(max) is achieved within 0.5-4.0 h postdose. Steady-state plasma concentrations are achieved after 7 consecutive days of dosing. Although the pharmacokinetics of maraviroc is nonproportional over the dose range studied (3-1200 mg), the degree of nonproportionality is small at clinically relevant doses. Renal clearance is approximately 10-12 l h(-1) and appears unaffected by increasing maraviroc doses. Maraviroc does not significantly modulate the activity of CYP2D6 or CYP3A4 at clinically relevant doses. There were no serious adverse events in any of these studies, and doses up to 900 mg were generally well tolerated, with postural hypotension being the dose-limiting event. There was no pattern or dose relationship observed with maraviroc with regard to laboratory abnormalities, including hepatic transaminases. No clinically significant increases in QTc were noted at clinically relevant doses. CONCLUSIONS: Maraviroc is absorbed into the systemic circulation and reaches steady state by day 7 of multiple dosing. It does not significantly influence the activity of major drug-metabolizing enzymes and is well tolerated at clinically relevant doses, with most adverse events being mild or moderate.

Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjects.

AIMS: Two studies were conducted to: (i) quantify the amount of drug-related radioactivity in blood, plasma, urine and faeces following a (14)C-labelled dose of maraviroc; and (ii) investigate the pharmacokinetics, safety and tolerability of intravenous (i.v.) maraviroc and determine the absolute bioavailability of oral maraviroc. Metabolite profiling was also conducted. Data from both of these studies were used to construct a mass-balance model for maraviroc. METHODS: Study 1 was an open-label study in three healthy male subjects. All subjects received a single 300-mg oral solution dose of (14)C-labelled maraviroc. Study 2 included two cohorts of subjects. Cohort 1 involved a double-blind (third party open), four-way crossover study where eight subjects received escalating i.v. doses of maraviroc (3, 10 and 30 mg) with placebo insertion. Cohort 2 involved an open, two-way crossover study where 12 subjects received 30 mg maraviroc by i.v. infusion and 100 mg maraviroc orally in random order. In study 1, blood samples and all urine and faeces were collected up to at least 120 h postdose. In study 2, blood samples were taken at intervals up to 48 h postdose. Urine was also collected up to 24 h postdose in cohort 1 only. RESULTS: After oral administration in study 1, maraviroc was rapidly absorbed with a plasma T(max) reached by 2 h postdose for all three subjects. The maximum concentrations of radioactivity also occurred within 2 h for all subjects. There was a higher amount of radioactivity in plasma than in blood (blood/plasma ratio approximately 0.6 for AUC(t) and C(max)). Unchanged maraviroc was the major circulating component in plasma, accounting for approximately 42% of the circulating radioactivity. Following a 300-mg (14)C-labelled maraviroc dose, means of 76.4% and 19.6% of radioactivity were recovered in the faeces and urine, respectively. The mean total recovery of dosed radioactivity was 96%, with the majority of radioactivity being recovered within 96 h postdose. Profiling of the urine and faeces showed similar and extensive metabolism in all subjects. Unchanged maraviroc was the major excreted component (33%). The major metabolic pathways were determined and involved oxidation and N-dealkylation. Intravenous doses of maraviroc (3-30 mg) were well tolerated in study 2, and drug exposure was approximately proportional to dose within the studied range. Approximately 23% of total clearance (44 l h(-1)) was accounted for by renal clearance (10.2 l h(-1)). Mean volume of distribution at steady state was 194 l. Absolute bioavailability of a 100-mg oral tablet dose, by comparison with a 30-mg i.v. dose, was calculated to be 23.1%. CONCLUSIONS: Maraviroc is rapidly absorbed and extensively metabolized, although unchanged maraviroc is the major circulating component in plasma and is the major excreted component after oral dosing. The pharmacokinetics of maraviroc after i.v. administration is approximately proportional over the dose range studied. Renal clearance contributes 23% of total clearance. The absolute bioavailability of 100 mg oral maraviroc is 23%.

A pharmacokinetic-pharmacodynamic model to optimize the phase IIa development program of maraviroc.

OBJECTIVES: To use a viral dynamics model to compare the effectiveness of in vivo viral inhibition of several doses of maraviroc (MVC;UK-427,857) and to use a modeling approach to support design decisions for a monotherapy study using various dosing regimens of maraviroc given with and without food. DESIGN: The pharmacokinetic-pharmacodynamic model was developed using clinical data from a first monotherapy study (study A4001007). This was a randomized, double-blind, placebo-controlled, multicenter study of maraviroc in 44 asymptomatic HIV-1-infected patients. Patients received maraviroc under food restrictions at 25 mg once daily or 50, 100, or 300 mg twice daily, or placebo for 10 days. METHODS: Antiviral responses were assessed by measuring plasma HIV-1 RNA levels during screening, during randomization, at baseline, and daily during the 10 days of treatment and at days 11 to 15, 19, 22, 25, and 40. An integrated pharmacokinetic-pharmacodynamic model was developed using the mixed effects modeling approach with patients' pharmacokinetic profiles on the last day of treatment, HIV-1 RNA levels over time, and the individual viral susceptibility. The parameters derived from the viral dynamic model were used to calculate average viral inhibition fraction, decay rate of actively infected cells, and basic reproductive ratio for each treatment group. Monte Carlo simulation was then used to determine the distribution of viral load change across simulated patients over time for each regimen to be studied in another monotherapy study, A4001015. RESULTS: The decline rate in the 300 mg twice daily group was comparable to that induced by potent protease inhibitor monotherapy, but was significantly slower than that in patients receiving combination therapy including both protease inhibitor and reverse transcriptase inhibitors. The efficacy of inhibition in vivo was estimated to range from 0.15 to 0.38 for the 25 mg once daily dose group and from 0.88 to 0.96 for the 300 mg twice daily dose group. CONCLUSIONS: The model has aided the analysis and interpretation of the clinical data. The use of a model-based approach for selecting doses can accelerate drug development by replacing some arms or trials with simulations.