Anita Mathias

A phase 1, randomized, placebo-controlled, 3-day, dose-ranging study of GS-5885, an NS5A inhibitor, in patients with genotype 1 hepatitis C

BACKGROUND & AIMS GS-5885 is an inhibitor of the hepatitis C virus (HCV) NS5A protein and exhibits potent suppression of genotype 1 HCV replicons. The safety, tolerability, pharmacokinetics, antiviral activity, and resistance profile of once-daily GS-5885 doses of 1-90 mg were evaluated in patients with chronic genotype 1 HCV. METHODS Genotype 1 HCV-infected patients were randomized to 3 days of once-daily (QD) dosing with placebo (n=12) or GS-5885 1 mg (n=10), 3 mg (n=10), 10 mg (n=20), 30 mg (n=10), or 90 mg (n=10). Plasma samples for pharmacokinetics, HCV RNA, and NS5A sequencing were collected through day 14. RESULTS GS-5885 was well tolerated and resulted in median maximal reductions in HCV RNA ranging from 2.3 log(10) IU/ml (1 mg QD) to 3.3 log(10) IU/ml (10 mg QD in genotype 1b and 30 mg QD). E(max) modeling indicated GS-5885 30 mg was associated with>95% of maximal antiviral response to HCV genotype 1a. HCV RNA reductions were generally more sustained among patients with genotype 1b vs. 1a. Three of 60 patients had a reduced response and harbored NS5A-resistant virus at baseline. NS5A sequencing identified residues 30 and 31 in genotype 1a, and 93 in genotype 1b as the predominant sites of mutation following GS-5885 dosing. Plasma pharmacokinetics was consistent with QD dosing. CONCLUSIONS During 3 days of monotherapy, low doses of GS-5885 demonstrated significant antiviral activity in genotype 1a and 1b HCV-infected patients. GS-5885 is currently being evaluated in combination with direct antiviral regimens with and without peginterferon.

Pharmacokinetics and Pharmacodynamics of GS‐9350: A Novel Pharmacokinetic Enhancer Without Anti‐HIV Activity

GS‐9350 is a new chemical entity under development as a potent, mechanism‐based inhibitor of human cytochrome P450 3A (CYP3A) isoforms. Its intended use is to increase the systemic exposure of coadministered agents that are metabolized by CYP3A enzymes. Unlike ritonavir, which is in current clinical use for this purpose, GS‐9350 is devoid of anti‐HIV activity. The pharmacokinetics of GS‐9350 and its efficacy in increasing systemic exposure of the probe CYP3A substrate midazolam were examined in a study involving single‐ and multiple‐dose escalations of GS‐9350 from 50 to 400 mg. Single‐dose escalation from 50 to 400 mg resulted in a 164‐fold increase in GS‐9350 exposure, whereas multiple‐dose escalation in the dosage range of 50–300 mg resulted in a 47‐fold increase in exposure. GS‐9350 potently inhibited midazolam apparent clearance (95% reduction), similar in effect to ritonavir 100 mg. GS‐9350 was generally well tolerated at all doses, and there was no evidence of dose‐limiting toxicity. Establishing proof‐of‐concept, GS‐9350 is currently under phase II development as a potential alternative to ritonavir for use with antiretroviral agents (including the HIV integrase inhibitor elvitegravir) that are often prescribed along with a “booster” drug.

Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function.

Objective:This study evaluated the effect of cobicistat (COBI) on glomerular filtration rate in subjects with normal renal function (RF) or with mild/moderate renal impairment, by comparing creatinine clearance [estimated glomerular filtration rate (eGFR)] with actual GFR (aGFR) using iohexol, a probe drug excreted by glomerular filtration. COBI is a potent CYP3A inhibitor (pharmacoenhancer) currently in phase 3 testing with elvitegravir, atazanavir, and darunavir. Methods:Normal RF subjects received COBI 150 mg QD, ritonavir (RTV) 100 mg QD, or placebo for 7 days; subjects with mild/moderate renal impairment received COBI 150 mg QD. The eGFR and aGFR were measured on days 0, 7, and 14 and within-subject changes calculated relative to day 0. COBI and RTV pharmacokinetics were analyzed on day 7. Results:All 36 subjects in cohort 1 and 17 of 18 subjects in cohort 2 completed all study treatments. Study treatments were well tolerated. Small increases in serum creatinine with corresponding mean decreases in eGFR (∼10 mL/min or mL/min per 1.73 m2) were observed on day 7 relative to day 0 in subjects receiving COBI (P < 0.05). The decreases were reversible on COBI discontinuation; mean eGFR values returned to baseline on day 14 (P > 0.05). No statistically significant changes in aGFR on days 7 or 14 relative to day 0 were seen with COBI (P > 0.05). No statistically significant decreases in aGFR or eGFR were observed with RTV or placebo. Conclusions:COBI affects eGFR but not the actual GFR. The time to onset, magnitude, and time to resolution of changes in eGFR are consistent with altered proximal tubular secretion of creatinine through inhibition of drug transporters.

Clinical Pharmacokinetic and Pharmacodynamic Profile of the HIV Integrase Inhibitor Elvitegravir

Elvitegravir is a potent, boosted, once-daily, HIV integrase inhibitor with antiviral activity against wild-type and drug-resistant strains of HIV. Because elvitegravir is metabolized primarily by cytochrome P450 (CYP) 3A enzymes, coadministration with a strong CYP3A inhibitor such as ritonavir or cobicistat (also known as GS-9350), an investigational pharmacoenhancer, substantially increases (boosts) elvitegravir plasma exposures and prolongs its elimination half-life to ∼9.5 hours, allowing once-daily administration of a low 150 mg dose. Boosting also results in low intra- and intersubject pharmacokinetic variability and high elvitegravir trough concentrations (∼6- to 10-fold above the concentration producing 95% inhibition of wild-type HIV-1 virus [IC95] of 45 ng/mL [protein binding-adjusted]), which is the pharmacokinetic parameter best associated with its antiviral activity.Data from extensive evaluation of the potential for boosted elvitegravir to undergo drug-drug interactions with other antiretroviral agents or concomitant medications indicate the absence of clinically relevant interactions or the need for dose modification in several cases, except for dose reduction of elvitegravir from 150 to 85 mg when coadministered with atazanavir/ritonavir or lopinavir/ritonavir. Dose adjustments for maraviroc and rifabutin, when each is coadministered with boosted elvitegravir, are consistent with their observed interactions with other ritonavir-boosted agents. The presence of a strong CYP3A inhibitor such as ritonavir or cobicistat renders the potential for increase in systemic exposures of CYP3A substrates coadministered with boosted elvitegravir. This article reviews a comprehensive pharmacology programme, including drug-drug interaction studies, mechanistic and special population studies, that has allowed a thorough understanding of elvitegravir clinical pharmacokinetics and its impact on pharmacodynamics.

Phase 2 study of cobicistat versus ritonavir each with once-daily atazanavir and fixed-dose emtricitabine/ tenofovir df in the initial treatment of HIV infection

Objective:To assess efficacy and safety of cobicistat versus ritonavir as pharmacoenhancers for atazanavir when administered with emtricitabine/tenofovir df as initial treatment for HIV-1 infection. Design:Randomized, partially placebo-controlled, double-blind, multicenter study. Participants:Antiretroviral treatment-naive adults, screening HIV-1 RNA of at least 5000 copies/ml and CD4 cell count more than 50 cells/&mgr;l. Intervention:Randomized 2 : 1 (stratified by HIV RNA ⩽ or >100 000 copies/ml) to receive placebo-blinded once-daily cobicistat 150 mg or ritonavir 100 mg with open-label atazanavir and fixed-dose emtricitabine/tenofovir df. Main outcome measures:Efficacy and safety at weeks 24 and 48. Results:Eighty-four percent of ATV/co participants and 86% of ATV/r participants suppressed HIV-1 RNA (<50 copies/ ml) at week 24, and 82 and 86% at week 48, respectively, and mean CD4 cell count increased 203 and 199 cells/&mgr;l at week 24 and 208 and 177 cells/&mgr;l at week 48, respectively. Study treatment discontinuation due to adverse events occurred in 4% ATV/co and in 3% ATV/r participants through 48 weeks. Treatment-related adverse events occurred in 36% ATV/co and 48% ATV/r participants; hyperbilirubinemia occurred in 96 and 100%, and ocular icterus or jaundice occurred in 14 and 17%, respectively. Mean estimated glomerular filtration rate (Cockcroft–Gault, ml/min) decrease occurred in both treatment groups and was evident at week 2 (ATV/co −9, ATV/r −4), reached a nadir by week 24 (−15, −14, respectively), and did not progress further through week 48 (−13, −14). Conclusion:Using cobicistat and ritonavir as pharmacoenhancers for atazanavir and administered with emtricitabine/tenofovir df achieved comparable rates of virologic suppression and CD4 cell count increase with satisfactory safety profiles.

Dose–Response of Ritonavir on Hepatic CYP3A Activity and Elvitegravir Oral Exposure

Ritonavir, a potent inhibitor of cytochrome P450 isoform 3A (CYP3A) activity, is frequently used to boost the effects of protease inhibitors at doses of 100–400 mg per day; however, human data regarding the optimal dose required for boosting are limited. This study systematically evaluated the ritonavir dose–response relationship on presystemic and systemic CYP3A metabolism using the human immunodeficiency virus integrase inhibitor elvitegravir and midazolam as probe substrates. Ritonavir administered once daily with elvitegravir exhibited nonlinear pharmacokinetics, with a 119‐fold increase in the area under the plasma concentration–time curve over the dosing interval over a 20‐ to 200‐mg dose range. The 20‐mg dose of ritonavir substantially reduced CYP3A‐mediated clearance (CL), as evidenced by a 66% reduction in midazolam CL that plateaued to 17% of baseline activity at a 100‐mg dose. Maximum inhibition of elvitegravir apparent oral CL was achieved with ritonavir doses of 50–100 mg. Elvitegravir and ritonavir were generally well tolerated in this study. These data provide a critical understanding of ritonavirs dose–response relationship for inhibition of CYP3A activity in humans.

Pharmacokinetics and Safety of Indinavir in Human Immunodeficiency Virus-Infected Pregnant Women

ABSTRACT Human immunodeficiency virus-infected women (n = 16) received indinavir (800 mg three times a day) plus zidovudine plus lamivudine from 14 to 28 weeks of gestation to 12 weeks postpartum. Two women and eight infants experienced grade 3 or 4 toxicities that were possibly treatment related. Indinavir area under the plasma concentration-time curve was 68% lower antepartum versus postpartum, suggesting increased intestinal and/or hepatic CYP3A activity during pregnancy.

Bioequivalence of efavirenz/emtricitabine/tenofovir disoproxil fumarate single-tablet regimen.

Objective:Efavirenz (EFV; 600 mg), emtricitabine (FTC; 200 mg) and tenofovir disoproxil fumarate (TDF; 300 mg) are preferred agents for treatment of HIV-1 infection in adults. This study evaluated the pharmacokinetics (PK) and bioequivalence of an investigational coformulation of EFV/FTC/TDF (test) single-tablet regimen compared with the commercially available individual dosage forms (EFV+FTC+TDF; reference treatment) in healthy subjects. Methods:Subjects were randomized to 1 of 2 treatment sequences (test→reference or reference→test) in an open-label crossover study design. Study drug was administered under fasted conditions, and serial blood samples were obtained over 504 hours after oral administration of each treatment. Formulation bioequivalence was assessed in accordance with the US Food and Drug Administration bioequivalence criteria. Results:Forty-eight subjects were enrolled, and 45 completed the study, with all study treatments being generally well tolerated. For EFV (n = 44), the geometric mean ratios (90% confidence interval [CI]) for maximum concentration (Cmax), area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC0-last), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) were 99.9 (93.4 to 107), 95.7 (90.5 to 101), and 95.2 (88.9 to 102), respectively. For FTC (n = 45), the geometric mean ratios (90% CI) for Cmax, AUC0-last, and AUCinf were 88.8 (84.0 to 93.9), 98.0 (94.9 to 101), and 98.0 (94.9 to 101), respectively. For tenofovir (n = 45), the geometric mean ratios (90% CI) for Cmax, AUC0-last, and AUCinf were 91.5 (84.6 to 98.8), 99.3 (91.0 to 108), and 100 (93.2 to 108), respectively. Conclusions:The coformulation of EFV/FTC/TDF is bioequivalent to administration of its individual components.

Pharmacokinetics and Safety of Stavudine in HIV-Infected Pregnant Women and Their Infants: Pediatric AIDS Clinical Trials Group Protocol 332

This study evaluates the safety, tolerance, and pharmacokinetics of stavudine (d4T) in human immunodeficiency virus (HIV)-infected zidovudine (ZDV)-intolerant/refusing pregnant women and of single-dose d4T in their infants. Women received d4T and lamivudine (3TC) from enrollment until labor. During labor, women received oral 3TC and either intravenous or oral d4T. Infants received ZDV and 3TC for 6 weeks and a single dose of oral d4T at weeks 1 and 6. Mean maternal antenatal d4T pharmacokinetics (terminal plasma half-life [T1/2], 83.5+/-16.8 min; area under the plasma-concentration time curve [AUC0-infinity), 81.6+/-22.0 microg.min/mL; n=6) were not significantly different from those during labor (T(1/2), 87.3+/-24.7 min; AUC0-infinity, 88.1+/-16.6 microg.min/mL; n=6). Umbilical-cord and maternal plasma concentrations were not significantly different from one another. The oral clearance of d4T in infants was significantly greater at week 6 versus week 1 (6.8+/-1.0 vs. 5.6+/-1.2 mL/min/kg). There were no toxicities, in women or infants, that required discontinuation or modification of the study drug. No infants had positive HIV viral diagnostic tests. d4T with or without 3TC is a potential alternative to ZDV for HIV-infected pregnant women.

Lack of Effect of Tenofovir Disoproxil Fumarate on Pharmacokinetics of Hormonal Contraceptives

Study Objective. To assess the potential for a drug‐drug interaction between a representative hormonal contraceptive (norgestimate‐ethinyl estradiol) and tenofovir disoproxil fumarate (tenofovir DF), a prodrug of tenofovir, when coadministered.