Pharmacokinetics of the anti-human immunodeficiency virus nucleoside analog stavudine in cynomolgus monkeys

Abstract

Stavudine was administered (15 mg/kg of body weight) intravenously and orally to two monkeys in a randomized crossover study. Plasma and urine samples were analyzed for stavudine by high-performance liquid chromatography, and pharmacokinetic parameters were derived by a noncompartmental method. Total body clearance of stavudine was 0.64 liters/h/kg, with a steady-state volume of distribution of 0.68 liters/kg, a terminal half-life of 0.83 h, a urinary recovery of 44%, and an oral bioavailability of 80%. These values were reasonably similar to those reported for patients with AIDS or AIDS-related complex.Zidovudine was the first nucleoside analog approved for the treatment of AIDS (28). The pharmacokinetics of zidovudine in humans (4,8,26,27,29) and various animal species (5,11,12,25,31) have been studied extensively. Studies with humans have shown that zidovudine is eliminated rapidly, with a terminal half-life (t1l2) of approximately 1 h, and about 60 to 80% of a dose is cleared from the body primarily by metabolism to the 5'-O-glucuronide. Of the animals investigated, the monkey has been identified as an appropriate animal model for zidovudine pharmacokinetics in humans (3, 5, 10, 11, 18) compared with other animals (11,18,19,37). Likewise, the monkey appears to be an acceptable model for didanosine pharmacokinetics in humans (33).Of several dideoxynucleoside analogs with in vitro antihuman immunodeficiency virus activity, stavudine has emerged as a potent agent which is being evaluated currently in clinical trials for the treatment of human immunodeficiency virus infection (2,14,15,32). The pharmacokinetics of stavudine in humans (13,22,24) and various animal species (6,7,35,36,38) have been reported previously.Studies with rodents have shown that the t1l2 of stavudine ranged from 0.3 to 0.6 h, the urinary recovery was about 70 to 80%, and the oral bioavailability was in the range of 80 to 95%. Although the t1l2 of stavudine in rhesus monkeys (0.9 to 1.4 h) is comparable to that in humans (13,22,24), interestingly, its absolute bioavailability is only 42% (versus 80 to 90% in humans) and the fractional urinary elimination of unchanged drug has not been reported. Therefore, the pharmacokinetics, oral bioavailability, and urinary excretion of stavudine in cynomolgus monkeys were evaluated to determine whether it is an appropriate model for stavudine pharmacokinetics in humans.Two young adult male cynomolgus monkeys weighing 2

Prenatal and postpartum pharmacokinetics of stavudine (2',3'-didehydro-3'-deoxythymidine) and didanosine (dideoxyinosine) in pigtailed macaques (Macaca nemestrina)

“…The pharmacokinetic parameters of stavudine and di-danosine are in general agreement with those previously reported for monkeys (3,7,18,19,21,22) and humans (5,6,8).…”

Disposition of [1′-14C]Stavudine after Oral Administration to Humans

“…The route of elimination in humans is in concurrence with the findings in mice, rats, and monkeys (Russell et al, 1990;Cretton et al, 1993;Kaul and Dandekar, 1993;Kaul et al, 1999). The extent of absorption and oral bioavailability of stavudine in humans was at least 95 and 67%, respectively, based on urinary recovery values of TRA and stavudine.…”

“…14 C]stavudine, [4- 14 C]stavudine, or [5-3 H]stavudine (all labels on the thymidine moiety) showed that the compound was well absorbed (Russell et al, 1990;Cretton et al, 1993;Kaul and Dandekar, 1993;Kaul et al, 1999). The recovery of the drug in excreta varied in animals, with the majority of the dose recovered in the urine.…”

Pharmacokinetics of the Anti-Human Immunodeficiency Virus Agent 1-(β-d-Dioxolane)Thymine in Rhesus Monkeys

“…The oral dose of 60 mg/kg was used for AZT and D4T with rhesus monkeys (7,39). Oral bioavailabilities of D4T were 25 to 51% in rhesus monkeys (39), 77 to 83% in cynomolgus monkeys (25), and almost 100% in humans and mice (36,38). High C max values were observed with APD, the DXG prodrug, after oral administration (C max of DXG ϭ 50 to 60 M within 0.25 to 0.5 h) (11) ; k 21 ϭ 0.51 h Ϫ1 ) are suggestive of rapid equilibration of the drug between the central and peripheral compartments.…”