Several relative bioavailability studies of lamivudine (3TC) in HIV-infected children (0.5-12y) showed that EPIVIR® oral solution yielded 30-57% lower plasma 3TC exposures than various tablet formulations. It was hypothesized that the lower 3TC concentrations observed in these pediatric studies could be due to an interaction between 3TC and sorbitol, an excipient in co-administered liquid medications. This study was conducted to evaluate the effect of sorbitol on the single dose pharmacokinetics (PK) of 3TC oral solution.
Study 204857 (NCT02634073) was an open label, randomized, 4-way William’s crossover study in healthy adult subjects. Subjects were randomized to receive each treatment in 1 of 4 sequences with a ≥7 day between-treatment washout period. Treatments included a single dose of 3TC 300 mg (Treatment A; reference), 3TC 300 mg + sorbitol 3.2 g (Treatment B), 3TC 300 mg + sorbitol 10.2 g (Treatment C), and 3TC 300 mg + sorbitol 13.4 g (Treatment D). 3TC was administered as EPIVIR 10mg/mL oral solution following an 8-hour fast. Serial PK samples were collected after each treatment. Test/reference geometric least squares (GLS) means ratio and associated 90% confidence intervals (CI) of non-compartmental PK parameters (log-transformed) were determined by analysis of variance using a mixed effects model. Safety assessments were performed throughout the study.
Of 37 subjects screened, 16 were randomized and completed the study. Selected 3TC PK parameters and statistical comparisons to reference are summarized in the Table. Sorbitol had a dose-dependent effect on 3TC PK with 28%, 52%, and 55% lower Cmax, 20%, 39%, and 44% lower AUC(0-24), and 14%, 32%, and 36% lower AUC(0-∞) when co-administered with 3.2 g, 10.2 g, and 13.4 g sorbitol, respectively. The median 3TC Tmax occurred between 0.75 to 1.26 h post dose, with later Tmax associated with sorbitol co-administration. 3TC with and without sorbitol containing solutions were well tolerated. There were no deaths or SAEs. A total of 3 subjects reported 5 AEs; 1 was drug-related.
Co-administration of single doses of 3TC and sorbitol solutions under fasted conditions resulted in decreased 3TC plasma exposures. Sorbitol had the greatest impact on 3TC Cmax and AUC(0-24), suggesting that an absorption-based interaction is the likely mechanism for the reduction in 3TC exposures observed in this study.