Background:  Pediatric fixed-dose combinations are urgently needed to facilitate antiretroviral therapy in children. A novel chewable pediatric fixed-dose combination has been developed by Thai Government Pharmaceutical Organization (GPO) composed of stavudine (d4T; 7 mg) + lamivudine (3TC; 150 mg) + nevirapine (NVP; 50 mg), and called GPOvir-S7. We report the bioavailability, safety, and therapeutic adequacy of GPOvir-S7 compared to the individual brand name liquid formulations in HIV-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. We enrolled and randomized 35 children weighing ≥6 to ≤30 kg, receiving NVP-based HAART and stable for at least 4 weeks, to receive either GPOvir-S7 tablets or d4T+3TC+NVP original liquid formulations. Children were stratified by weight:  Group 1 ≥6 to 8 kg (n = 3), Group 2 >8 to 16 kg (n = 8), Group 3 >16 to 23 kg (n = 12), and Group 4 >23 to 30 kg (n = 12). Dosing was based on body weight. Intensive 12-hour blood sampling for pharmacokinetics was performed on day 28, then subjects crossed-over to the alternate formulation at equal doses for 28 days. On day 56, a second 12-hour sampling for pharmacokinetics was performed. Plasma levels for d4T, 3TC, and NVP were determined by high-performance liquid chromatography (HPLC) and pharmacokinetic parameters by non-compartmental analysis. Therapeutic inadequacy of GPOvir-S7 was based on the location of the 90%CI for the mean area under the curve (AUC). If the 90%CI lay within 70 to 143% of the target mean, AUC therapeutic adequacy was declared.

Results:  A total of 34 children complete the pharmacokinetic sampling. No sequence or carryover effects were observed. None of the 3 drug exposures for GPOvir-S7 was deemed therapeutically inadequate. The median NVP predose level was 5.4 mg/L for both GPOvir-S7 and the liquid formulation:  3 of 34 (8%) children had a predose level <3.0 mg/L (range 1.9 to 2.8 mg/L) with both formulations. No serious drug-related toxicity was reported. 

Conclusions:  The novel chewable GPOvir-S7 fixed-dose combinations was safe and provided therapeutically adequate plasma drug levels in HIV-infected children. Substituting the liquid formulations with GPOvir-S7 could be considered to help simplify ART.