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

Important note: Information in this article was accurate in 1999. The state of the art may have changed since the publication date.

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

Drug Metab Dispos. 1999 Jan;27(1):41-5. Unique Identifier : AIDSLINE MED/99102131
Balani SK; Kauffman LR; deLuna FA; Lin JH; Department of Drug Metabolism, Merck Research Laboratories, West; Point, Pennsylvania 19486, USA.

Abstract: Efavirenz (EFV, Sustiva, Stocrin, DMP-266, L-743,726) is a potent and selective non-nucleoside inhibitor of HIV-1 reverse transcriptase. Pharmacokinetics 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, Vdss, and T1/2 were 67 ml/min/kg, 5.0 liters/kg, and 1 h, respectively. EFV was metabolized 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 monkeys, 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 species led to disproportionate increases in the AUC and higher Tmax values, suggesting saturation of metabolism and/or prolongation of absorption. The delay in Tmax was more pronounced in monkeys where the plasma concentrations reached plateaus and were sustained for 4 to 20 h. In rats, the prolongation of absorption was due to delayed gastric emptying as demonstrated by >10-fold slower transit of [14C]polyethylene glycol through the stomach of 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 results demonstrated that in rats and monkeys, both delayed gastric emptying and saturation of metabolic processes played significant roles in the nonlinear pharmacokinetics of EFV.

Keywords: JOURNAL ARTICLE Animal Anti-HIV Agents/*PHARMACOKINETICS Area Under Curve Biological Availability Comparative Study Half-Life HIV-1/*DRUG EFFECTS/ENZYMOLOGY HIV-1 Reverse Transcriptase/*METABOLISM Macaca mulatta Male Metabolic Clearance Rate Oxazines/*PHARMACOKINETICS Rats Rats, Sprague-Dawley Reverse Transcriptase Inhibitors/*PHARMACOKINETICS
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A9950882

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