Methadone and buprenorphine pharmacokinetics and pharmacodynamics when coadministered with fostemsavir to opioid-dependent, human immunodeficiency virus seronegative participants.

AIMS: Regional human immunodeficiency virus (HIV) prevalence rates are high in people with history of injection drug use, including those managed with maintenance opioids. Fostemsavir (FTR) is an oral prodrug of temsavir, a first-in-class attachment inhibitor that binds HIV-1 gp120, preventing initial HIV attachment and entry into host immune cells. Here we determine the impact of FTR on the pharmacokinetics of opioids methadone (MET: R-, S- and total) or buprenorphine and norbuprenorphine (BUP and norBUP) when coadministered. METHODS: Study 206216 (NCT02666001) was a Phase I, open-label study, assessing the effect of FTR 600 mg (extended-release formulation) twice daily on pharmacokinetics of MET or BUP and norBUP, in non-HIV-infected participants on stable maintenance therapy with MET (40-120 mg; n = 16) or BUP plus naloxone (8-24 mg plus 2-6 mg; n = 16); pharmacodynamic response was assessed using standard opioid rating scales. RESULTS: Following coadministration with FTR, dose-normalized MET (R-, S- and total) exposures (maximum concentration in plasma, area under the plasma concentration-time curve over the dosing interval and concentration in plasma at 24 hours) increased 9-15% and BUP and norBUP exposures increased 24-39%. The 90% confidence interval ranges for MET (1.01-1.21) and BUP and norBUP (1.03-1.69) were within respective no-effect ranges (0.7-1.43 and 0.5-2.0). Opioid pharmacodynamic scores were similar with and without MET/BUP with no symptoms of withdrawal/overdose; no new safety signal for FTR when combined with a stable opioid regimen. CONCLUSIONS: FTR did not impact MET and had no clinically significant impact on BUP pharmacokinetics. Standardized assessments of opioid pharmacodynamics were unchanged throughout FTR administration with MET or BUP. FTR can be administered with MET or BUP without dose adjustment.

The Effects of Clarithromycin on the Pharmacokinetics of Apixaban in Healthy Volunteers: A Single-Sequence Crossover Study.

BACKGROUND: This was an open-label, phase I, nonrandomized, single-sequence, crossover study to evaluate the effect of concomitant administration of multiple doses of clarithromycin on the single-dose exposure, safety, and tolerability of apixaban in healthy subjects. METHODS: In total, 19 subjects received a single oral dose of apixaban 10 mg on day 1. On day 4, subjects began receiving oral clarithromycin immediate release (IR) 500 mg twice daily (bid) for 4 days. On day 8, subjects received oral apixaban 10 mg and oral clarithromycin IR 500 mg bid. Oral clarithromycin IR 500 mg bid was given alone on days 9 and 10. RESULTS: Compared with apixaban alone, coadministration of apixaban with clarithromycin resulted in increased apixaban exposure. The adjusted geometric mean ratio (GMR) was 1.299 (90% confidence interval [CI] 1.220-1.384) for peak plasma concentration (Cmax), whereas the adjusted GMR for the area under the concentration curve (AUC(INF)) was 1.595 (90% CI 1.506-1.698). The mean half-life and median time to Cmax of apixaban were comparable with and without concomitant administration of clarithromycin. Administration of apixaban and clarithromycin concomitantly did not result in increased adverse events compared with administration of either agent alone. All adverse events were mild in intensity. CONCLUSIONS: Apixaban Cmax and AUC(INF) increased 30% and 60%, respectively, when multiple doses of clarithromycin were coadministered with apixaban versus administration of apixaban alone. The increase in apixaban Cmax and AUC(INF) with concomitant clarithromycin was less than that which has been observed when apixaban was given with ketoconazole. Administration of apixaban alone and in combination with clarithromycin bid was safe and generally well-tolerated by the healthy adult subjects in this study. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier number NCT02912234.

Effects of a Fixed-Dose Co-Formulation of Daclatasvir, Asunaprevir, and Beclabuvir on the Pharmacokinetics of a Cocktail of Cytochrome P450 and Drug Transporter Substrates in Healthy Subjects.

BACKGROUND: A fixed-dose combination of daclatasvir (DCV; hepatitis C virus NS5A inhibitor), asunaprevir (ASV; non-structural protein 3 inhibitor), and beclabuvir (BCV; non-structural protein 5B inhibitor) is approved in Japan for hepatitis C virus genotype 1. OBJECTIVE: The objective of this study was to assess the combination's drug-drug interaction potential in vivo using a validated cocktail of eight cytochrome P450 (CYP) and transporter probes. METHODS: We conducted an open-label single-sequence study in healthy adults (n = 20) given single-dose caffeine (CYP1A2 substrate), metoprolol (CYP2D6), flurbiprofen (CYP2C9), montelukast (CYP2C8), omeprazole (CYP2C19), midazolam (CYP3A4), digoxin (P-glycoprotein), and pravastatin (organic anion-transporting polypeptide), alone or with steady-state twice-daily DCV/ASV/BCV 30/200/75 mg (with or without additional BCV 75 mg to adjust for higher exposure in hepatitis C virus infection). RESULTS: Daclatasvir/asunaprevir/beclabuvir did not affect CYP1A2, CYP2C8, or CYP2C9; the probe maximum observed concentration and area under the concentration-time curve extrapolated to infinite time geometric mean ratios and 90% confidence intervals were all within the 0.8-1.25 bioequivalence range. Beclabuvir showed moderate dose-dependent CYP2C19 induction; omeprazole maximum observed concentration and area under the concentration-time curve from 0 to the last quantifiable concentration were lower with additional BCV [geometric mean ratio 0.36 (90% confidence interval 0.23-0.55) and 0.34 (0.25-0.46), respectively] than without [0.57 (0.42-0.78), 0.48 (0.39-0.59)]. Weak-to-moderate CYP3A4 induction was observed, plus weak CYP2D6, P-glycoprotein, and organic anion-transporting polypeptide inhibition [maximum observed concentration and area under the concentration-time curve extrapolated to infinite time without additional BCV: midazolam 0.57 (0.50-0.65), 0.53 (0.47-0.60); metoprolol 1.40 (1.20-1.64), 1.71 (1.49-1.97); digoxin 1.23 (1.12-1.35), 1.23 (1.17-1.29); pravastatin 2.01 (1.63-2.47), 1.68 (1.43-1.97)]. CONCLUSIONS: No dose adjustments with DCV/ASV/BCV are indicated for CYP1A2, CYP2C8, CYP2C9, or P-glycoprotein substrates. CYP3A4, CYP2D6, and OATP substrates should be co-administered with caution. Co-administration with agents solely metabolized by CYP2C19 is not recommended.