The results of two randomized, single‐dose, crossover bioavailability studies are presented which describe the pharmacokinetics and oral bioavailability of nevirapine, a novel nonnucleoside antiretroviral drug. In the first study 12 healthy male volunteers received nevirapine 15 mg via short‐term i.v. infusion or orally as a 50 mg tablet or reference solution (50 mg/200 mL). Following the i.v. dose, nevirapine had a low systemic clearance (Mean±S.D., Cl=1.4±0.3 L/h) and a prolonged elimination phase (t1/2β=52.8±14.8 h; MRT=81.4±22.4 h). Nevirapine absolute bioavailability was 93±9% and 91±8% for the tablet and oral solution, respectively. In the second study, 24 healthy male volunteers were administered nevirapine as a 200 mg production‐line tablet or oral reference solution (200 mg/200 mL). There was no significant difference in bioavailability between the tablet and reference solution. Overall, comparison of the pharmacokinetic parameters between the 50 and 200 mg doses indicates that nevirapine is well absorbed at clinically relevant doses. The absorption profiles using deconvolution revealed no evidence of differential enzyme induction between the two doses or routes of administration following a single dose. Copyright © 1999 John Wiley & Sons, Ltd.

Clinical Pharmacology & Therapeutics (1999) 65, 137–137; doi:

No abstract

The drug-drug interaction (DDI) potential of deleobuvir, an hepatitis C virus (HCV) polymerase inhibitor, and its two major metabolites, CD 6168 (formed via reduction by gut bacteria) and deleobuvir-acyl glucuronide (AG), was assessed in vitro. Area-under-the-curve (AUC) ratios (AUCi/AUC) were predicted using a static model and compared with actual AUC ratios for probe substrates in a P450 cocktail of caffeine (CYP1A2), tolbutamide (CYP2C9), and midazolam (CYP3A4), administered before and after 8 days of deleobuvir administration to HCV-infected patients. In vitro studies assessed inhibition, inactivation and induction of P450s. Induction was assessed in a short-incubation (10 hours) hepatocyte assay, validated using positive controls, to circumvent cytotoxicity seen with deleobuvir and its metabolites. Overall, P450 isoforms were differentially affected by deleobuvir and its two metabolites. Of note was more potent CYP2C8 inactivation by deleobuvir-AG than deleobuvir and P450 induction by CD 6168 but not by deleobuvir. The predicted net AUC ratios for probe substrates were 2.92 (CYP1A2), 0.45 (CYP2C9), and 0.97 (CYP3A4) compared with clinically observed ratios of 1.64 (CYP1A2), 0.86 (CYP2C9), and 1.23 (CYP3A4). Predictions of DDI using deleobuvir alone would have significantly over-predicted the DDI potential for CYP3A4 inhibition (AUC ratio of 6.15). Including metabolite data brought the predicted net effect close to the observed DDI. However, the static model over-predicted the induction of CYP2C9 and inhibition/inactivation of CYP1A2. This multiple-perpetrator DDI scenario highlights the application of the static model for predicting complex DDI for CYP3A4 and exemplifies the importance of including key metabolites in an overall DDI assessment.