Pharmacokinetics and Safety of a New Paediatric Fixed-Dose Combination of Zidovudine/Lamivudine/Nevirapine in HIV-Infected Children

Abstract

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.

Effect of Sorbitol on the Pharmacokinetic Profile of Lamivudine Oral Solution in Adults: An Open‐Label, Randomized Study

“…The results of this drug interaction study in adults implicate sorbitol as the perpetrator and underlying mechanism for the lower plasma lamivudine exposures in the aforementioned relative bioavailability studies in children with HIV‐1 infection who received repeated doses of lamivudine oral solution in combination with other antiretroviral drug formulations that contained sorbitol as an excipient 4, 6, 7. In each of those pediatric studies, lamivudine oral solution was coadministered with abacavir solution, which is formulated with high concentrations of sorbitol (340 mg/mL).…”

“…This study was designed to address the question of whether sorbitol affects the PK of lamivudine and therefore explain the findings of reduced exposures in children administered lamivudine in combination with other sorbitol‐containing medications 4, 6, 7…”

“…For children <14 kg without access to generic pediatric‐strength tablets or older children who are unable to swallow tablets, an upward dose adjustment from 8 mg/kg per day to 10 mg/kg per day of lamivudine solution may be appropriate if product labeling permits a dose increase. This 25% dose increase was based on the PK results of prior relative bioavailability studies in children receiving sorbitol4, 6, 7 and assumed that an increase in dose would overcome the sorbitol interaction in a proportional manner in order to achieve plasma lamivudine exposures that are similar to those reported in adults at the efficacious dose of 300 mg once daily. The 25% increase in dose was also supported by population PK modeling and simulation of pediatric data performed by Janssen et al .,19 who concluded that a dose of 10 mg/kg per day was appropriate for children ages 5 months to 18 years who weigh <14 kg.…”

“…In contrast with the pediatric findings, an earlier relative bioavailability study in adults demonstrated that lamivudine solution provided equivalent exposures to lamivudine tablets and capsules when both the test and reference formulations were administered alone 5. Additionally, two relative bioavailability studies of pediatric‐strength, three‐drug, fixed‐dose combination tablet formulations that were conducted in children (aged 0.5–12 years) showed that lamivudine solution given in combination with either stavudine/nevirapine or zidovudine/nevirapine liquid formulations had 29% or 44% lower lamivudine exposures than lamivudine administered as part of a three‐drug tablet,6, 7 despite these three‐drug tablet formulations having been shown to be equivalent to solutions in adult relative bioavailability studies 8, 9. Unlike studies in adults, the pediatric relative bioavailability studies were conducted in children being treated for HIV‐1 with lamivudine in combination with one or more antiretroviral drugs.…”

Nevirapine Exposure with WHO Pediatric Weight Band Dosing: Enhanced Therapeutic Concentrations Predicted Based on Extensive International Pharmacokinetic Experience

“…In both studies, children received combination therapy with the appropriate FDC tablet (referred to as GPO-VIR), which contained NVP and two NRTIs, and an equivalent innovator liquid formulation. Following intensive PK sampling with seven plasma samples obtained over the dosing interval, patients were crossed over to the alternate formulation, and a repeat intensive PK profile was obtained (3,26).…”