A series of dipyridodiazepinones have been shown to be potent inhibitors of human immunodeficiency virus-1 (HIV-1) reverse transcriptase (RT). One compound, BI-RG-587, had a Ki of 200 nanomolar for inhibition of HIV-1 RT that was noncompetitive with respect to deoxyguanosine triphosphate. BI-RG-587 was specific for HIV-1 RT, having no effect on feline and simian RT or any mammalian DNA polymerases. BI-RG-587 inhibited HIV-1 replication in vitro as demonstrated by in situ hybridization, inhibition of protein p24 production, and the lack of syncytia formation in cultured human T cell lines and freshly isolated human peripheral blood lymphocytes. Cytotoxicity studies of BI-RG-587 on human cells showed a high therapeutic index (greater than 8000) in culture.

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...

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