No differences in the pharmacodynamics and pharmacokinetics of the thrombin receptor antagonist vorapaxar between healthy Japanese and Caucasian subjects.

BACKGROUND: Vorapaxar, a novel antiplatelet agent in advanced clinical development for the prevention and treatment of atherothrombotic disease, is a potent, orally bioavailable thrombin receptor antagonist selective for the protease-activated receptor 1 (PAR-1). METHODS: Since race/ethnicity may affect the safety, efficacy and dosage of drugs, this study was conducted to evaluate potential differences in the pharmacodynamics, pharmacokinetics and safety of vorapaxar after single (5, 10, 20, or 40 mg) or multiple (0.5, 1, or 2.5 mg once daily) doses in healthy Japanese and matched (gender, age, height, and weight) Caucasian volunteers. RESULTS: Vorapaxar was well tolerated in both Japanese and Caucasian subjects. Pharmacodynamic and pharmacokinetic profiles of vorapaxar in the two racial/ethnic groups were similar. In both racial groups, complete inhibition of platelet aggregation was achieved most rapidly with vorapaxar 40 mg and was consistently achieved and maintained with a 2.5 mg daily maintenance dose. CONCLUSION: There were no substantial differences in the safety, pharmacokinetics or pharmacodynamics of vorapaxar between Japanese and Caucasian subjects.

Precision and accuracy in the quantitative analysis of biological samples by accelerator mass spectrometry: application in microdose absolute bioavailability studies.

Determination of the pharmacokinetics and absolute bioavailability of an experimental compound, SCH 900518, following a 89.7 nCi (100 µg) intravenous (iv) dose of (14)C-SCH 900518 2 h post 200 mg oral administration of nonradiolabeled SCH 900518 to six healthy male subjects has been described. The plasma concentration of SCH 900518 was measured using a validated LC-MS/MS system, and accelerator mass spectrometry (AMS) was used for quantitative plasma (14)C-SCH 900518 concentration determination. Calibration standards and quality controls were included for every batch of sample analysis by AMS to ensure acceptable quality of the assay. Plasma (14)C-SCH 900518 concentrations were derived from the regression function established from the calibration standards, rather than directly from isotopic ratios from AMS measurement. The precision and accuracy of quality controls and calibration standards met the requirements of bioanalytical guidance (U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Veterinary Medicine. Guidance for Industry: Bioanalytical Method Validation (ucm070107), May 2001. http://www.fda.gov/downloads/Drugs/GuidanceCompilanceRegulatoryInformation/Guidances/ucm070107.pdf ). The AMS measurement had a linear response range from 0.0159 to 9.07 dpm/mL for plasma (14)C-SCH 900158 concentrations. The CV and accuracy were 3.4-8.5% and 94-108% (82-119% for the lower limit of quantitation (LLOQ)), respectively, with a correlation coefficient of 0.9998. The absolute bioavailability was calculated from the dose-normalized area under the curve of iv and oral doses after the plasma concentrations were plotted vs the sampling time post oral dose. The mean absolute bioavailability of SCH 900518 was 40.8% (range 16.8-60.6%). The typical accuracy and standard deviation in AMS quantitative analysis of drugs from human plasma samples have been reported for the first time, and the impact of these parameters on quantitative analysis was further assessed using the Z factor. The use of the lowest achievable LLOQ(Z=0) derived from statistical analysis of the control and low-concentration standards for AMS measurements is proposed in future studies.

Effect of vicriviroc on the QT/corrected QT interval and central nervous system in healthy subjects.

Vicriviroc is a CCR5 antagonist in clinical development for the treatment of HIV-1. Two phase I studies were conducted to assess the safety of vicriviroc. One study characterized the drug's potential to prolong the QT/corrected QT (QTc) interval and to induce arrhythmia. In this partially blind, parallel-group study, 200 healthy subjects aged 18 to 50 years were randomized in equal groups to the following regimens: (i) placebo for 9 days and a single dose of moxifloxacin at 400 mg on day 10, (ii) placebo, (iii) vicriviroc-ritonavir (30 and 100 mg), (iv) vicriviroc-ritonavir (150 and 100 mg), and (v) ritonavir (100 mg). The second study characterized the effects of a range of vicriviroc doses on the central nervous system (CNS). In this third-party-blind, parallel-group study, 30 healthy subjects aged 18 to 48 years were randomized to receive a single dose of either vicriviroc at 200, 250, or 300 mg or placebo, followed by multiple (seven) once-daily doses of either vicriviroc at 150, 200, or 250 mg or placebo, respectively. In the first study, vicriviroc produced no clinically meaningful effect on the QT/QTc interval when administered at a supratherapeutic or therapeutic dose concurrently with ritonavir. In the second study, vicriviroc produced no observable seizure activity, nor was it held to be associated with any clinically relevant changes in brain waveforms in the final consensus of reviewers. These findings showed that vicriviroc produced no clinically relevant QTc prolongation cardiac or epileptogenic effects in healthy individuals at exposures as high as five times those expected for HIV-infected patients receiving therapeutic doses of vicriviroc in a ritonavir-boosted protease inhibitor-containing regimen.

Pomalidomide: evaluation of cytochrome P450 and transporter-mediated drug-drug interaction potential in vitro and in healthy subjects.

Pomalidomide offers an alternative for patients with relapsed/refractory multiple myeloma who have exhausted treatment options with lenalidomide and bortezomib. Little is known about pomalidomide's potential for drug-drug interactions (DDIs); as pomalidomide clearance includes hydrolysis and cytochrome P450 (CYP450)-mediated hydroxylation, possible DDIs via CYP450 and drug-transporter proteins were investigated in vitro and in a clinical study. In vitro pomalidomide was neither an inducer nor inhibitor of CYP450, nor an inhibitor of transporter proteins P glycoprotein (P-gp), BCRP, OAT1, OAT3, OCT2, OATP1B1, and OATP1B3. Oxidative metabolism of pomalidomide was predominately mediated by CYP1A2 and CYP3A4, and pomalidomide was shown to be a P-gp substrate. In healthy males, co-administration of oral (4 mg) pomalidomide with ketoconazole (CYP3A/P-gp inhibitor) or carbamazepine (CYP3A/P-gp inducer) did not result in clinically relevant changes in pomalidomide exposure. Co-administration of pomalidomide with fluvoxamine (CYP1A2 inhibitor) in the presence of ketoconazole approximately doubled pomalidomide exposure. Pomalidomide appears to have low potential for clinically relevant DDI and is unlikely to affect the clinical exposure of other drugs. Avoid co-administration of strong CYP1A2 inhibitors unless medically necessary. Pomalidomide dose should be reduced by 50% if co-administered with strong CYP1A2 inhibitors and strong CYP3A/P-gp inhibitors.

Foraging activity of two species of predatory leeches exposed to active and sedentary prey.

The foraging activity of the freshwater leeches Nephelopsis obscura and Erpobdella punctata during acclimation to active or sedentary prey, starvation and refeeding was examined by filming over a 24 h cycle. For both species, the time of activity of individual leeches and the total number of leeches active were significantly correlated. Activity in the dark was significantly higher than in the light with the activity of N. obscura in the dark 16.2 times higher in terms of time and 6.7 times higher in terms of numbers of individuals moving than E. punctata. Large N. obscura were significantly more active than medium or small individuals and encountered more sedentary prey. With lower levels of activity E. punctata encounters and feeds on more active prey, and in lotic ecosystems its lower exposure to fish predation and drift is, at least partially, responsible for its numerical abundance over N. obscura. There were no significant differences in the activity of N. obscura or E. punctata fed on active or sedentary prey during either subsequent starvation of 1 to 10 d, or after refeeding, suggesting that unchanged foraging activity provides the optimun net energy gain during periods of change in prey type and availability.

No clinically significant drug interactions between lenalidomide and P­glycoprotein substrates and inhibitors: results from controlled phase I studies in healthy volunteers.

PURPOSE: Lenalidomide, a weak substrate of P-glycoprotein (P-gp) in vitro, is an oral anticancer drug eliminated predominantly via renal excretion as unchanged compound. The role of P-gp in lenalidomide disposition and the associated clinical relevance were evaluated. METHODS: Two phase I, crossover studies were conducted in healthy volunteers. In Study 1, subjects received lenalidomide (10 mg × 7 days) alone or with the P-gp substrate digoxin (0.5 mg on Day 5). In Study 2, subjects received lenalidomide (a single 25 mg dose) alone, the P-gp inhibitor quinidine (300-600 mg twice-daily × 5 days) plus lenalidomide (on Day 4), the P-gp inhibitor/substrate temsirolimus (a single 25 mg dose) alone, or lenalidomide plus temsirolimus. Pharmacokinetic and safety data were collected for lenalidomide and the co-administrated drugs. RESULTS: There were no significant changes in the maximum concentration (C max) and area under the plasma concentration-time curve (AUC) of lenalidomide when co-administered with quinidine, digoxin, or temsirolimus. Neither the rate nor the capacity of lenalidomide renal excretion was affected by quinidine or temsirolimus, in addition lenalidomide absorption rate and bioavailability remained unchanged. Furthermore, lenalidomide had no significant effect on blood C max and AUC of temsirolimus and its active metabolite sirolimus (also a P-gp inhibitor/substrate). The C max of digoxin was slightly higher (+14 %) when administered with lenalidomide versus placebo. There were no other changes in digoxin pharmacokinetics upon co-administration with lenalidomide. No remarkable safety findings were observed. CONCLUSIONS: There are no clinically significant pharmacokinetic interactions between lenalidomide and substrates or inhibitors of P-gp.

Lenalidomide at therapeutic and supratherapeutic doses does not prolong QTc intervals in the thorough QTc study conducted in healthy men.

The effect of lenalidomide on the corrected QT (QTc) interval was evaluated in healthy men and extended to patients based on the lenalidomide concentration-QTc (C-QTc) relationship. A rigorous assessment of the effect of lenalidomide on QTc intervals was conducted in healthy volunteers who each received, in randomized order, a single oral dose of 10 mg lenalidomide, 50 mg lenalidomide, 400 mg moxifloxacin (positive control) and placebo. Plasma lenalidomide exposure was compared between healthy volunteers and patients with multiple myeloma or myelodysplastic syndromes. In healthy volunteers, moxifloxacin produced the expected significant prolongation in QTcI (individual correction). For lenalidomide 10 mg and 50 mg, the time-matched changes from placebo in the baseline-adjusted least-squares mean QTcI were <3 ms with the upper limit of the two-sided 90% confidence interval for the change <10 ms at all time-points. No subjects experienced QTcI >450 ms or change from baseline >60 ms after lenalidomide administration. Similar results were seen with QT interval data corrected by Fridericia and Bazett methods. The C-QTc analysis yielded no significant association between lenalidomide concentrations and QTcI changes up to 1522 ng/mL; this range was close to that observed in patients receiving lenalidomide doses up to 50 mg, including those with reduced drug clearance due to renal impairment. In conclusion, single doses of lenalidomide up to 50 mg were not associated with prolonged QTc intervals in healthy males. The C-QTc analysis further assured that lenalidomide doses up to 50 mg are not expected to prolong QTc intervals in patients.

Absorption, metabolism and excretion of [14C]pomalidomide in humans following oral administration.

PURPOSE: To investigate the pharmacokinetics and disposition of [(14)C]pomalidomide following a single oral dose to healthy male subjects. METHODS: Eight subjects were administered a single 2 mg oral suspension of [(14)C]pomalidomide. Blood (plasma), urine and feces were collected. Mass balance of radioactivity and the pharmacokinetics of radioactivity, pomalidomide and metabolites were determined. Metabolite profiling and characterization was performed. The enzymes involved in pomalidomide metabolism and the potential pharmacological activity of metabolites were evaluated in vitro. RESULTS: Mean recovery was 88 %, with 73 and 15 % of the radioactive dose excreted in urine and feces, respectively, indicating good oral absorption. Mean C(max), AUC(0-∞) and t(max) values for pomalidomide in plasma were 13 ng/mL, 189 ng*h/mL and 3.0 h. Radioactivity and pomalidomide were rapidly cleared from circulation, with terminal half-lives of 8.9 and 11.2 h. Pomalidomide accounted for 70 % of the circulating radioactivity, and no circulating metabolite was present at >10 % of parent compound. Pomalidomide was extensively metabolized prior to excretion, with excreted metabolites being similar to those observed in circulation. Clearance pathways included cytochrome P450-mediated hydroxylation with subsequent glucuronidation (43 % of the dose), glutarimide ring hydrolysis (25 %) and excretion of unchanged drug (10 %). 5-Hydroxy pomalidomide, the notable oxidative metabolite, was formed primarily via CYP1A2 and CYP3A4. The hydroxy metabolites and hydrolysis products were at least 26-fold less pharmacologically active than pomalidomide in vitro. CONCLUSIONS: Following oral administration, pomalidomide was well absorbed, with parent compound being the predominant circulating component. Pomalidomide was extensively metabolized prior to excretion, and metabolites were eliminated primarily in urine.

Single-dose pharmacokinetics of boceprevir in subjects with impaired hepatic or renal function.

BACKGROUND AND OBJECTIVE: Boceprevir is a novel inhibitor of the hepatitis C virus NS3 protease and was recently approved for the treatment of patients with chronic hepatitis C infection. The objective of this study was to evaluate the impact of impaired hepatic or renal function on boceprevir pharmacokinetics and safety/tolerability. METHODS: We conducted two open-label, single-dose, parallel-group studies comparing the safety and pharmacokinetics of boceprevir in patients with varying degrees of hepatic impairment compared with healthy controls in one study and patients with end-stage renal disease (ESRD) on haemodialysis with healthy controls in the other. Patients with hepatic impairment (mild [n = 6], moderate [n = 6], severe [n = 6] and healthy controls [n = 6]) received a single dose of boceprevir (400 mg) on day 1, and whole blood was collected at selected timepoints up to 72 hours postdose to measure plasma drug concentrations. Patients with ESRD and healthy subjects received a single dose of boceprevir 800 mg orally on days 1 and 4, with samples for pharmacokinetic analyses collected at selected timepoints up to 48 hours postdose on both days. In addition, 4 hours after dosing on day 4, patients with ESRD underwent haemodialysis with arterial and venous blood samples collected up to 8 hours postdose. RESULTS: In the hepatic impairment study, there was a trend toward increased mean maximum (peak) plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC) of boceprevir with increasing severity of liver impairment. Point estimates for the geometric mean ratio for C(max) ranged from 100% in patients with mild hepatic impairment to 161% in patients with severe hepatic impairment, with the geometric mean ratio for AUC ranging from 91% in patients with mild hepatic impairment to 149% for patients with severe hepatic impairment, relative to healthy subjects. The mean elimination half-life (t(1/2;)) and median time to C(max) (t(max)) values of boceprevir were similar in healthy subjects and patients with hepatic impairment. In the renal impairment study, mean boceprevir C(max) and AUC values were comparable in patients with ESRD and in healthy subjects, with point estimates for the geometric mean ratio of 81% and 90%, respectively, compared with healthy subjects. Mean t(1/2;), median t(max) and mean apparent oral total clearance (CL/F) values were similar in healthy subjects and patients with ESRD. Boceprevir exposure was also similar in patients with ESRD on day 1 (no dialysis) and day 4 (dialysis beginning 4 hours postdose), with point estimates for the geometric mean ratio of C(max) and AUC to the last measurable sampling time (AUC(last)) on day 1 compared with day 4 of 88% and 98%, respectively. Treatment-emergent adverse events were reported in one patient with severe hepatic impairment (mild vomiting) and two patients with ESRD (moderate ventricular extrasystoles, flatulence and catheter thrombosis). CONCLUSION: In the present studies, the pharmacokinetic properties of boceprevir were not altered to a clinically meaningful extent in patients with impaired liver or renal function. These data indicate that boceprevir dose adjustment is not warranted in patients with impaired hepatic function or ESRD, including those receiving dialysis. Boceprevir is not removed by haemodialysis.

Pharmacokinetic interaction of vicriviroc with other antiretroviral agents: results from a series of fixed-sequence and parallel-group clinical trials.

BACKGROUND: Vicriviroc is a next-generation antiretroviral compound that blocks HIV from entering uninfected cells by binding to the virus's cellular co-receptor chemokine receptor 5 (CCR5). A potent inhibitor of HIV infection of human cells both in vitro and in vivo, vicriviroc is in development for use in treatment-naïve HIV-1-infected individuals. These patients often receive antiretroviral therapy regimens that include a ritonavir-enhanced protease inhibitor. Such regimens have a high potential for drug-drug interactions because many of the antiretroviral agents inhibit or induce elements of drug elimination pathways, such as the hepatic cytochromes, which may alter drug concentrations and affect both safety and efficacy. The aim of this set of studies was to determine what, if any, dose adjustments or monitoring would be required to use vicriviroc in regimens containing the most common antiretroviral agents. METHODS: Drug-drug interactions between vicriviroc and 11 other antiretroviral compounds were investigated in fixed-sequence or parallel-group clinical trials lasting 12-35 days. Fixed-sequence studies were conducted with the protease inhibitors atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, saquinavir and tipranavir. In these studies vicriviroc was administered with ritonavir for a fixed duration, followed by administration of vicriviroc with ritonavir plus the protease inhibitor. Parallel-group studies conducted with lopinavir, zidovudine/lamivudine and tenofovir disoproxil fumarate randomized subjects to receive vicriviroc with or without the study drug. All subjects enrolled in the studies were healthy male and female adults. STATISTICAL METHODS: The log-transformed data for vicriviroc primary pharmacokinetic parameters on appropriate days were statistically analysed using a one-way analysis of variance (ANOVA) model extracting the effects due to treatment. Steady state was evaluated by an ANOVA model on trough concentrations using day and subject as class variables. RESULTS: Vicriviroc exposure was not affected by the concurrently administered antiretroviral drugs in any clinically relevant manner, nor did vicriviroc have a clinically relevant effect on the exposure of other drugs. The drug combinations studied were safe and well tolerated, with most adverse events reported as mild to moderate. Aside from the known toxicities of the other antiretroviral drugs, no clinically relevant changes in blood chemistry, haematological parameters, ECGs or vital signs were associated with either vicriviroc or combination treatment. CONCLUSIONS: No dose modification or monitoring of vicriviroc concentrations is necessary when vicriviroc is co-administered with any of the antiretroviral agents reviewed here. The lack of drug-drug interactions suggests that it will be possible to add vicriviroc at the single clinically prescribed dose level to various background regimens that include a boosted protease inhibitor, with all other drugs also prescribed at their standard doses.

Effect of vicriviroc with or without ritonavir on oral contraceptive pharmacokinetics: a randomized, open-label, parallel-group, fixed-sequence crossover trial in healthy women.

BACKGROUND: Because women of childbearing potential represent 20% to 25% of the HIV population, it is important to determine any potential drug interactions between vicriviroc, an antiretroviral agent, and an oral contraceptive (OC) to provide guidance on any potential dose adjustments. OBJECTIVE: The primary study objective was to determine the effect of vicriviroc, a C-C chemokine receptor type 5 inhibitor, alone or in the presence of ritonavir, on the pharmacokinetics (AUC and C(max)) of the study OC (ethinyl estradiol [EE] 0.035 mg + norethindrone [NET] 1 mg). A secondary objective was to monitor the safety and tolerability of vicriviroc plus an OC with and without ritonavir. METHODS: This was a randomized, open-label, parallel-group, single-center study with a fixed-sequence crossover design. Female subjects were randomized into 2 groups and treated for 2 menstrual cycles. In cycle 1, all received the OC alone, per standard 28-day pack instructions. On the first 10 days of cycle 2, group 1 received OC + vicriviroc and group 2 received OC + ritonavir; on the following 11 days, both groups received OC + vicriviroc + ritonavir. Blood samples were collected up to 24 hours after dosing on prespecified days. Pharmacokinetic parameters, including AUC(0-24), C(max), and C(min), were calculated using noncompartmental methods, and drug interactions were evaluated using an ANOVA model by treatment group. Adverse events were collected using physical examination, vital sign measurements, clinical laboratory analysis, electrocardiography, and questioning at predefined time points throughout the study to assess the safety profile. RESULTS: Twenty-seven subjects were enrolled (26 white, 1 black). The median age and body mass index were 21 years (range, 18-36 years) and 24.5 kg/m(2) (range, 19.1-31.3 kg/m(2)), respectively. Twenty-one subjects completed the study and were included in the pharmacokinetic analysis; 4 discontinued for reasons unrelated to study drug and 2 discontinued because of adverse events. Vicriviroc had little effect on the pharmacokinetics of the OC. EE mean ratio estimates for C(max) and AUC(0-24) compared with OC administered alone were 91% and 97%, respectively, and for NET were 106% and 93%. Subjects receiving ritonavir, alone or with vicriviroc, experienced decreases in exposure of EE (C(max) mean ratio estimates, 89% and 76%; AUC(0-24) mean ratio estimates, 71% each, for ritonavir alone and ritonavir with vicriviroc, respectively) and, to a lesser extent, decreases in NET (C(max) mean ratio estimates 89% each; AUC(0-24) mean ratio estimates: 93% and 83%, for ritonavir alone and ritonavir with vicriviroc, respectively). Twenty-two of 27 (81%) subjects reported ≥1 treatment-emergent adverse event (TEAE). During cycle 1, TEAEs were reported for 18 of 27 (67%) subjects while receiving OC alone and for 3 of 24 (13%) subjects while receiving placebo OC. During cycle 2, TEAEs were reported for 8 of 12 (67%) subjects while receiving vicriviroc with OC, 4 of 12 (33%) subjects while receiving ritonavir with OC, 7 of 22 (32%) subjects while receiving vicriviroc + ritonavir with OC, and 2 of 22 (9%) subjects while receiving placebo OC. The most commonly reported TEAE was headache (vicriviroc + OC, n = 1; ritonavir + OC, n = 3; vicriviroc + ritonavir + OC, n = 2; OC alone, n = 12; placebo OC, n = 2). No TEAEs were considered severe. CONCLUSIONS: In this population of healthy female subjects, vicriviroc had little effect on the pharmacokinetics of EE or NET, whereas ritonavir, alone or with vicriviroc, was associated with consistent decrease in exposure of EE and a lesser decrease in NET.

Renal insufficiency has no effect on the pharmacokinetics of vicriviroc in a ritonavir-containing regimen.

BACKGROUND AND OBJECTIVE: Vicriviroc is a small-molecule CCR5 antagonist currently in development for the treatment of HIV in patients on a regimen containing a ritonavir-boosted protease inhibitor. As renal disease and renal dysfunction are prevalent in the HIV-infected population, patients with varying degrees of renal insufficiency may receive vicriviroc, which is metabolized by cytochrome P450 (CYP) 3A4. The present study therefore examined the impact of renal insufficiency on the pharmacokinetics and safety of vicriviroc alone and in the presence of ritonavir, a strong CYP3A4 inhibitor. SUBJECTS AND METHODS: This study was an open-label, randomized, two-treatment crossover trial conducted in HIV-negative subjects with haemodialysis-dependent end-stage renal disease (ESRD) and healthy subjects with normal renal function matched by age, height, bodyweight and sex. Subjects received a single dose of vicriviroc 75 mg alone in one period, and in another period they received a single dose of vicriviroc 15 mg after 4 days of ritonavir 100 mg once daily. Ritonavir treatment was then continued for an additional 13 days. The two trial periods were separated by an interval of at least 3 weeks. The primary endpoints were the log-transformed area under the plasma concentration-time curve (AUC) and the maximum plasma concentration (C(max)), and the 90% confidence intervals (CIs) of the mean differences between subjects with ESRD and matched healthy subjects. The protocol provided the option of dose modification and further study if the vicriviroc C(max) and AUC values were at least twice as high in subjects with ESRD compared with healthy subjects, or if warranted by other safety and tolerability observations. RESULTS: Twelve subjects (six with ESRD, six healthy) completed the study. When vicriviroc was administered alone, the mean vicriviroc C(max) and AUC ratio estimates (90% CI) for subjects with ESRD versus healthy subjects were 74% (53, 103) and 84% (49, 145), respectively. When ritonavir was added to the regimen, the ratio estimates (90% CI) were 81% (59, 111) and 134% (105, 171), respectively. Ritonavir plasma concentrations were substantially higher in subjects with ESRD than in healthy subjects. Treatment-emergent adverse events considered possibly or probably related to treatment occurred only during the ritonavir period of the study and in one healthy subject and two subjects with ESRD; all were of mild or moderate severity. CONCLUSIONS: ESRD had no clinically relevant impact on exposure of vicriviroc when vicriviroc was administered alone or in the presence of ritonavir. In this single-dose study, vicriviroc was well tolerated both by healthy subjects and by those with ESRD. Dose adjustment of vicriviroc is therefore not necessary in renally impaired populations.

Short-term administration of the CCR5 antagonist vicriviroc to patients with HIV and HCV coinfection is safe and tolerable.

OBJECTIVE: CCR5 antagonists block HIV cell entry through competitive binding to the CCR5 receptor present on the surface of CD4(+) cells. The CCR5 receptor is also present on CD8(+) cells involved in clearing hepatitis C virus (HCV). The goal of the present study was to examine the short-term safety of a CCR5 antagonist, vicriviroc, in patients with HIV/HCV coinfection. METHODS: A randomized, double-blind trial was conducted in 28 HIV/HCV-coinfected subjects with compensated liver disease and plasma HIV RNA below 400 copies/mL. All subjects were receiving a ritonavir-enhanced protease inhibitor regimen, to which vicriviroc (5, 10, or 15 mg/day) or placebo was added for 28 days. Clinical and laboratory evaluations were performed 21 days beyond the treatment period. RESULTS: Treatment with vicriviroc resulted in no clinically meaningful changes in HCV or HIV viral load or any immune parameters. Adverse events were equally distributed among placebo and vicriviroc groups. Transaminase elevations of grade 1 or more were reported as AEs in 1 subject receiving 10-mg vicriviroc and 1 placebo subject. Vicriviroc plasma concentrations were similar to those observed in healthy subjects. CONCLUSIONS: Short-term treatment with vicriviroc as part of a ritonavir-containing protease inhibitor-based regimen was safe and well tolerated in HIV/HCV-coinfected subjects. HIV/HCV coinfection also did not affect vicriviroc pharmacokinetics.