Pharmacokinetics of nevirapine: initial single-rising-dose study in humans

Abstract

Nevirapine, a nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, was administered for the first time to humans in a pilot study designed to investigate the pharmacokinetics and tolerance of the drug following single-dose administration to 21 HIV-1-infected individuals. The study followed a parallel design. Different groups of three subjects each were given one of seven dose levels (2.5 to 400 mg) in sequential order, starting with the lowest dose. Each subject received only one dose. Nevirapine was rapidly absorbed at all doses from a tablet formulation. Peak concentrations in plasma were generally achieved within 90 min of dose administration. Secondary peaks were also noted between 3 and 12 h or between 24 and 28 h, the latter being noted mainly in subjects receiving the higher doses. After 24 h, concentrations in plasma declined in a log-linear fashion. The terminal half-life and mean residence time exceeded 24 h in all but one subject, indicating a prolonged disposition time in this population. Both peak concentrations in plasma and areas under the plasma concentration-time curves increased proportionally with increasing dose from 2.5 to 200 mg; however, the increase in the peak concentration in plasma and the area under the plasma concentration-time curve appeared to be less than proportional at the 400-mg dose level in this small number of subjects. This observation may be due to increased clearance or decreased absorption at the highest dose or population differences in absorption or clearance between doses. Studies with a cross-over design are planned to resolve these issues. The pharmacokinetic characteristics of nevirapine are appropriate for once-daily administration. A daily 12.5-mg dose is predicted to achieve trough concentrations in plasma in the range required to totally inhibit replication of wild-type HIV-1 in human T-cell culture.Nevirapine, formerly known as BI-RG-587, is a potent nonnucleoside reverse transcriptase inhibitor specific for human immunodeficiency virus type 1 (HIV-1) (7) which shows good characteristics for development as a potential therapeutic agent. The 50% inhibitory concentration (IC50) in human T-cell culture is 10.6 mg/ml (40 nM) and the therapeutic index is 8,000 (6). Nevirapine in combination with zidovudine exhibits synergistic antiviral activity without increased cytotoxicity (11). The structure of nevirapine is shown in Fig. 1 showed hydroxylation at several sites, the major oxidative metabolite being hydroxymethyl-nevirapine. In chimpanzee, rat, and dog, the urinary excretion of parent drug was low, suggesting liver metabolism as the major route of clearance.Induction of cytochrome P-450 2B1 (phenobarbital-inducible) and 3A (alcohol-inducible) isozymes occurred in rats after repeated dosing at 10 mg/kg and higher (2). However, short-term safety studies in rats and dogs showed no toxicities which would preclude development of the compound.The objectives of the present study were to generate initial information on nevirapine...

Population pharmacokinetics of nevirapine in combination with rifampicin-based short course chemotherapy in HIV- and tuberculosis-infected South African patients

“…Enterohepatic recycling of nevirapine has been shown in rats [37] and is suggested to be present in humans due to the presence of a second peak concentration following the administration of oral and intravenous single doses [32,38,39]. In this study, a second peak concentration was seen in some patients, but not in others who may have eaten at times different from the sampling times.…”

Intracellular Metabolism and Persistence of the Anti-Human Immunodeficiency Virus Activity of 2′,3′-Didehydro-3′-Deoxy-4′-Ethynylthymidine, a Novel Thymidine Analog

“…Interestingly, in our persistence studies the 4Ј-Ed4T percent inhibition was superior to that of NVP. Single-dose NVP is used to prevent mother-to-child transmission of HIV in resource-limited settings because of its cost-effectiveness and favorable pharmacokinetics (half-life of 30 h) (2,4,16).…”

“…To evaluate the intracellular thymidine analog metabolites, CEM cells (2 ϫ 10 7 /ml) were incubated with 2 M (75 mCi/mmol) of the various radiolabeled thymidine analogs in medium comprised of RPMI 1640 with 10% dialyzed fetal bovine serum and 100 g/ml kanamycin at 37°C in 5% CO 2 for 24 h as previously described (15,53). At different time intervals (2,4,8,12,16, and 24 h), 2 ϫ 10 7 of the cells were harvested by centrifugation and washed twice in ice-cold phosphate-buffered saline containing 20 M dipyridamole (Sigma). The cell pellets were extracted with 15% trichloroacetic acid for 15 min on ice.…”

Inhibitory Effect of Individual or Combinations of Broadly Neutralizing Antibodies and Antiviral Reagents against Cell-Free and Cell-to-Cell HIV-1 Transmission

“…HIV-1 inhibitors were all obtained from the NIH AIDS Reagent Program and dissolved in dimethyl sulfoxide (DMSO). They included the gp41-directed fusion inhibitor T-20 (61), the C-C chemokine receptor 5 (CCR5)-directed entry inhibitor maraviroc (62), the CCR5 receptor antagonist TAK-779 (63,64), and the nucleoside-and nonnucleoside reverse transcriptase (RT) inhibitors PMPA {9[R-2-(phosphonylmethoxy) propyl] adenine monohydrate} (65) and nevirapine (66), respectively. The starting concentrations of each inhibitor used in the inhibition assays were based on their previously documented half-maximal inhibitory concentrations (IC 50 s) (61,62,(64)(65)(66).…”