Background:  An extended release formulation of nevirapine (NVP) 100-mg and 400-mg tablets has been developed to allow once-daily dosing, which may improve treatment convenience and adherence, while maintaining the predicated target steady state mean trough NVP plasma concentration (C_pre,ss) around 3000 ng/mL. This study assessed the steady-state pharmacokinetics of once-daily NVP extended release compared to twice-daily NVP immediate release in HIV-1-infected children.

Methods:  A phase I, open-label, multi-dose, cross-over study in patients aged ≥3 to <18 years, previously treated for ≥18 weeks with an immediate-release NVP -based regimen and viral load <50 copies/mL at baseline. Patients were stratified by age group (3 to <6, 6 to <12, 12 to <18 years), and switched to extended-release NVP based on the immediate-release NVP dose calculated by body weight or body surface area. Extended-release daily doses were 200 mg, 300 mg (as 100-mg tablets) or 400 mg (as 1 x 400-mg tablet). Patients were treated with twice-daily immediate-release NVP (tablets or suspension) for 11 days, then extended-release NVP for 10 days. C_pre,ss was obtained from all patients, while steady-state 12-hour and 24-hour pharmacokinetic profiles were obtained for immediate release and extended release, respectively, for patients enrolled in the pharmacokinetic sub-study. Viral suppression was monitored and adverse events recorded.

Results:  Of the 85 patients who participated in the trial, 80 (91.4%) completed it, 74 had C_pre,ss, and 45 had intensive pharmacokinetic data available for analysis. The adjusted geometric mean C_pre,ss values for NVP extended release and NVP immediate release (4149 and 4518 ng/mL respectively) exceeded the target C_pre,ss. The adjusted geometric mean extended-release : immediate-release ratios for daily dose normalized (ng/mL/mg/day) and un-normalized C_pre,ss were 91.2% (90%CI 83 to 100%) and 91.8% (90%CI 84 to 101%), respectively, both with 90%CI within the bounds of 80 to 125%. Adjusted geometric mean 24-hour area under curve (AUC_t,ss) extended-release : immediate-release ratio for un-normalized dose was 90.3% (90%CI 82 to 99%). Un-normalized C_pre,ss extended-release : immediate-release ratios were 91.0%, 81.8%, and 103.7%, for the 3 to <6, 6 to <12, and 12 to <18 year age groups, respectively. Viral suppression was maintained for each age group during the study period. Incidence of any adverse events (including infections or infestations, skin or subcutaneous, and respiratory) was 47% with extended release and 28.2% with immediate release, mainly mild intensity, and similar between age groups. No adverse events of grade 4 (NIH Division of AIDS criteria), serious adverse events, or treatment discontinuations due to adverse events occurred.

Conclusions:  Once-daily dosing with extended-release NVP exhibited pharmacokinetic profiles that provided adequate C_pre,ss, with bioavailability for extended release relative to immediate release within the accepted range of bioequivalence, and was well tolerated in pediatric patients.