Pharmacokinetics of 3TC (GR109714X) Administered With and Without Food to HIV-infected Patients

3TC (GR109714X) is a new cytosine dideoxynucleoside analogue that has been shown to have in vitro activity against a variety of laboratory and clinical strains of HIV-1 including zidovudine (ZDV)-resistant isolates. Preclinical studies suggest that 3TC may have fewer adverse effects than other antiretroviral nucleoside analogues. An initial bioavailability study demonstrated that 3TC was rapidly and extensively absorbed following oral administration. Because the bioavailability of other nucleoside analogues is significantly affected when taken with food, we conducted a randomised 2-way crossover study to determine the pharmacokinetics of 3TC following a single oral 50mg dose with and without a standard fat meal in 12 HIV-infected men. In the absence of food, 3TC is rapidly absorbed with a time taken to reach maximum serum concentration (t_max) of 0.88 ± 0.25 hours and a mean maximum serum concentration (C_max) of 513 ± 215 ng/ml. In the presence of a standard fat meal, the t_max is delayed (3.15 ± 1.27 hours, p = 0.0001) and the C_max is decreased (273 ± 56 ng/ml, p = 0.0017). The total amount of drug absorbed into the systemic circulation as indicated by the area under the curve over 24 hours (AUC) is not significantly different in the fed and fasted states (fasting AUC = 1677 ±424 ng ∙ h/ml, fed AUC = 1548 ± 247 ng ∙ h/ml, p = 0.1347). This demonstrates that although absorption of 3TC is delayed and the maximal concentration is reduced in the presence of a standard fat meal, the amount of drug absorbed is not altered. The intersubject variability is also limited and certainly not increased when 3TC is taken with a meal. Because the activity profile is probably dependent upon systemic activity and not absorption rate, these data suggest that 3TC may be effectively administered to patients in fasting or fed states.