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.

Assessment of the cardiac safety of fampridine-SR sustained-release tablets in a thorough QT/QTc evaluation at therapeutic and supratherapeutic doses in healthy individuals.

OBJECTIVE: To characterize the effects of a sustained-release formulation of fampridine (fampridine-SR) on QT interval in healthy subjects. METHODS: In a double-blind, double-dummy trial, healthy subjects were randomized to 5 days treatment with fampridine-SR at therapeutic (10 mg twice daily) or supratherapeutic (30 mg twice daily) doses, placebo or moxifloxacin (400 mg on treatment day 5). Digital 12-lead electrocardiograms were recorded before treatment and on day 5; blood samples determined fampridine concentrations. Central tendency analysis determined whether the upper limit of the CI for the QT (individual-corrected QT; QTcI) interval change exceeded 10 ms. Outlier analysis determined new-onset QT (corrected QT; QTc) intervals; maximum change in QTc from baseline of 30 - 60 ms and maximum change from baseline >or= 60 ms. The relationship between pharmacokinetic parameters and QTcI values is explored. RESULTS: Moxifloxacin was associated with a QTcI interval increase > 5 ms at 7 time points; no increase was observed with either dose of fampridine-SR; there were no fampridine outliers. Pharmacokinetic evaluation failed to find dose-dependent cardiac effects. Fampridine was well tolerated, with a higher frequency of adverse events at the supratherapeutic dose. CONCLUSION: This study showed that fampridine-SR at therapeutic and supratherapeutic doses was not associated with QT prolongation in healthy subjects.