A Randomized Phase I Bioequivalence Clinical Trial of a Paediatric Fixed-Dose Combination Antiretroviral Reconstitutable Suspension in Healthy Adult Volunteers

Abstract

This study aimed to test the hypothesis that the paediatric fixed-dose combination granule for reconstitution (comprising lamivudine/zidovudine/nevirapine 30/60/50 mg per 5 ml) as a test product is bioequivalent to the coadministered single entities of the referenced products. Fixed-dose combination anti-retroviral therapy provides adequate suppression of HIV-1 replication, provides barrier to the development of resistance, simplifies dosage regimen and improves adherence. An open label, randomized, two-way crossover study was conducted on 24 health adults under fasted conditions, with a washout period of 14 days between treatments. A total of 15 blood samples were collected before dosing and up to 96 h post dosing. The drugs were extracted from plasma and anlaysed using a validated high performance liquid chromatography- ultraviolet method. Non- compartmental pharmacokinetic (PK) analysis was performed to obtain the PK parameters, maximum plasma concentration (C max), area under the curve of plasma concentration-time curves from the time zero to last measurable concentration (AUC0-t) and the area under the curve extrapolated to infinity (AUC 0-∞) ANOVA test was performed to determine the effect of model factors on the PK parameters. The two one-sided t-tests were performed on the log-transformed data to determine the 90% CL for the ratio of test to reference PK parameters. The drugs were well tolerated and safe with minimal adverse events. The ANOVA test indicated the absence of any significant effects ( P>0.05) due to the model parameters. The 90% Cl for the geometric mean ratio of the test/reference for the Cmax, AUC0-t and the AUC0-∞ for lamivudine, zidovudine and nevirapine were within 80-125% bioequivalence limits. This single dose randomized study found that the test and reference products met the criteria for bioequivalence in the fasting healthy adult volunteers.