Nonlinear pharmacokinetics of efavirenz (DMP-266), a potent HIV-1 reverse transcriptase inhibitor, in rats and monkeys

Efavirenz (EFV, Sustiva, Stocrin, DMP-266, L-743,726) is st potent and sele ctive non-nucleoside inhibitor of HIV-1 reverse transcriptase, Pharmacokine tics of EFV was studied in rats and monkeys, the safety assessment species, in rats, after 2 and 5 mg/kg i.v. administrations, the mean CLp, Vd(ss) an d T-1/2 were 67 ml/min/kg, 5.0 liters/kg, and 1 h, respectively. EFV was me tabolized completely, and the products were excreted almost exclusively via bile. At the higher dose of 15 mg/kg, the CLp was reduced by 36%, implying saturation of metabolism processes. A similar phenomenon occurred in monke ys, where the CLp declined by 60% as the i.v. dose was increased from 5 to 15 mg/kg. After oral dosing, the bioavailability of EFV in rats (10 mg/kg) and monkeys (2 mg/kg) was 16% and 42%, respectively. Higher doses in both s pecies led to disproportionate increases in the AUC and higher T-max values , suggesting saturation of metabolism and/or prolongation of absorption. Th e delay in T-max was more pronounced in monkeys where the plasma concentrat ions reached plateaus and were sustained for 4 to 20 h. In rats, the prolon gation of absorption was due to delayed gastric emptying as demonstrated by >10-fold slower transit of [C-14]polyethylene glycol through the stomach o f EFV-pretreated animals. The delayed gastric emptying in monkeys also was observed when the animals dosed at 160 mg/kg exhibited emesis, 8 h postdose , which was found to contain a substantial portion of the dose. These resul ts demonstrated that in rats and monkeys, both delayed gastric emptying and saturation of metabolic processes played significant roles in the nonlinea r pharmacokinetics of EFV.