A chewable pediatric fixed-dose combination tablet of stavudine, lamivudine, and nevirapine: pharmacokinetics and safety compared with the individual liquid formulations in human immunodeficiency virus-infected children in Thailand
Nirun Vanprapar, Tim R Cressey, Kulkanya Chokephaibulkit, Petronella Muresan, Nottasorn Plipat, Virat Sirisanthana, Wasana Prasitsuebsai, Suchat Hongsiriwan, Tawee Chotpitayasunondh, Achara Eksaengsri, MariPat Toye, Mary Elizabeth Smith, Kenneth McIntosh, Edmund Capparelli, Ram Yogev, IMPAACT P1056 Team, Nirun Vanprapar, Tim R Cressey, Kulkanya Chokephaibulkit, Petronella Muresan, Nottasorn Plipat, Virat Sirisanthana, Wasana Prasitsuebsai, Suchat Hongsiriwan, Tawee Chotpitayasunondh, Achara Eksaengsri, MariPat Toye, Mary Elizabeth Smith, Kenneth McIntosh, Edmund Capparelli, Ram Yogev, IMPAACT P1056 Team
Abstract
Background: Pediatric fixed-dose combinations (FDCs) are needed to facilitate antiretroviral therapy in children. We evaluated the relative bioavailability, safety, and therapeutic adequacy of a novel chewable pediatric FDC tablet of stavudine (7 mg), lamivudine (30 mg), and nevirapine (50 mg), referred to as GPO-VIR S7, and compared it with the individual original brand-name liquid formulations in human immunodeficiency virus-infected Thai children.
Methods: The International Maternal Pediatric Adolescent AIDS Clinical Trials group (IMPAACT) P1056 study was a phase I/II, 2-arm, randomized, open-label, multidose pharmacokinetic cross-over study. Children ≥6 to ≤30 kg receiving nevirapine-based HAART for at least 4 weeks were randomized to receive GPO-VIR S7 chewable tablets or the equivalent liquid formulations. Children were stratified by weight and dosing was weight-based. Intensive 12-hour blood sampling was performed on day 28, and subjects then crossed-over to the alternate formulation at equal doses with identical 12-hour sampling on day 56. Pharmacokinetic indices were determined by noncompartmental analysis.
Results: Thirty-four children completed the study. While taking Government Pharmaceutical Organization (GPO)-VIR S7 the geometric mean (90% CI) area under the curve was 1.54 μg·hr/mL (1.42-1.67) for stavudine, 6.39 (5.82-7.00) for lamivudine, and 74.06 (65.62-83.60) for nevirapine. Nevirapine drug exposure for GPO-VIR S7 was therapeutically adequate. Geometric mean area under the curve ratios (90% CI) of GPO-VIR S7/liquid formulation for stavudine, lamivudine, and nevirapine were 0.97 (0.92-1.02), 1.41 (1.30-1.53), and 1.08 (1.04-1.13), respectively. No serious drug-related toxicity was reported.
Conclusions: The chewable FDC was safe and provided therapeutically adequate plasma drug exposures in human immunodeficiency virus-infected children. Substituting the FDC for liquid formulations can simplify antiretroviral therapy.
Source: PubMed