A Chewable Pediatric Fixed-dose Combination Tablet of Stavudine, Lamivudine, and Nevirapine

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 immunode-ficiency virus-infected Thai 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.…”

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

“…Several d4T/3TC/NVP paediatric FDC tablets have been developed [6], including a chewable tablet developed by the Thai Government Pharmaceutical Organization (GPO) [7]. In 2008, the World Health Organization (WHO) Paediatric Antiretroviral Working Group highlighted the need for affordable, safe and high-quality antiretroviral FDC formulations for paediatric use and proposed several priority FDC combinations to be developed [8].…”