Pharmacokinetics and safety of a new paediatric fixed-dose combination of zidovudine/lamivudine/nevirapine in HIV-infected children.

BACKGROUND: Alternatives to the available stavudine-containing paediatric fixed-dose combination (FDC) tablets are rapidly needed due to concerns regarding the cumulative toxicity of long-term stavudine exposure. We report the bioavailability and short-term safety of a novel paediatric FDC tablet of zidovudine (ZDV)/lamivudine (3TC)/nevirapine (NVP; 30/15/28 mg) in HIV-infected children. METHODS: In this Phase I/II open-label pharmacokinetic study, 42 children weighing 6-30 kg treated with NVP-based HAART for ≥4 weeks were randomized to receive the FDC tablets (GPO-VIR Z30) or the liquid formulations. Dosing was weight-based. Intensive 12-h blood sampling was performed after 2 weeks; subjects then crossed-over to the alternate formulation at equal doses and sampling repeated 2 weeks later. Pharmacokinetic parameters were determined by non-compartmental analysis. Buccal-swab samples were collected for cytochrome P450 (CYP)2B6 polymorphism analysis. RESULTS: With the FDC tablet, the geometric mean (90% CI) area under the curve (AUC) for ZDV, 3TC and NVP was 1.58 (1.49-1.68), 7.78 (7.38-8.19) and 68.88 (62.13-76.36) µg•h/ml, respectively. Rules for NVP therapeutic inadequacy were defined a priori, and despite lower NVP exposure with the tablet (P<0.001), the levels remained therapeutically adequate. ZDV AUC was similar between formulations. 3TC exposure was significantly higher with the tablet but comparable to historical data in adults and children taking branded tablets. While receiving the tablet, NVP AUC in children with CYP2B 516 GG (45%), GT (45%) and TT (10%) genotypes were 67.0, 74.5 and 106.4 µg•h/ml, respectively (P=0.04). CONCLUSIONS: Disparities in drug exposure between formulations were observed; however, the FDC tablet delivered therapeutically adequate exposures of each drug and could well play an important role in simplifying antiretroviral treatment for children.

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.

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.

Evidence of human immunodeficiency virus-associated lipodystrophy syndrome in children treated with protease inhibitors.

We conducted a prospective evaluation for evidence of the HIV-associated lipodystrophy syndrome of 26 children infected with HIV-1. Six children had evidence of body fat redistribution. Nine children showed laboratory evidence of insulin resistance. All children with body fat distribution or insulin resistance had been treated with protease inhibitors. Children treated with protease inhibitors had higher total cholesterol, higher low density lipoprotein-cholesterol and higher triglycerides than untreated children.