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.
Full text
PDF
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Dressman J. B., Amidon G. L., Fleisher D. Absorption potential: estimating the fraction absorbed for orally administered compounds. J Pharm Sci. 1985 May;74(5):588–589. doi: 10.1002/jps.2600740523. [DOI] [PubMed] [Google Scholar]
- Koup R. A., Merluzzi V. J., Hargrave K. D., Adams J., Grozinger K., Eckner R. J., Sullivan J. L. Inhibition of human immunodeficiency virus type 1 (HIV-1) replication by the dipyridodiazepinone BI-RG-587. J Infect Dis. 1991 May;163(5):966–970. doi: 10.1093/infdis/163.5.966. [DOI] [PubMed] [Google Scholar]
- Merluzzi V. J., Hargrave K. D., Labadia M., Grozinger K., Skoog M., Wu J. C., Shih C. K., Eckner K., Hattox S., Adams J. Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science. 1990 Dec 7;250(4986):1411–1413. doi: 10.1126/science.1701568. [DOI] [PubMed] [Google Scholar]
- Nunberg J. H., Schleif W. A., Boots E. J., O'Brien J. A., Quintero J. C., Hoffman J. M., Emini E. A., Goldman M. E. Viral resistance to human immunodeficiency virus type 1-specific pyridinone reverse transcriptase inhibitors. J Virol. 1991 Sep;65(9):4887–4892. doi: 10.1128/jvi.65.9.4887-4892.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Richman D., Rosenthal A. S., Skoog M., Eckner R. J., Chou T. C., Sabo J. P., Merluzzi V. J. BI-RG-587 is active against zidovudine-resistant human immunodeficiency virus type 1 and synergistic with zidovudine. Antimicrob Agents Chemother. 1991 Feb;35(2):305–308. doi: 10.1128/aac.35.2.305. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Richman D., Shih C. K., Lowy I., Rose J., Prodanovich P., Goff S., Griffin J. Human immunodeficiency virus type 1 mutants resistant to nonnucleoside inhibitors of reverse transcriptase arise in tissue culture. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11241–11245. doi: 10.1073/pnas.88.24.11241. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shih C. K., Rose J. M., Hansen G. L., Wu J. C., Bacolla A., Griffin J. A. Chimeric human immunodeficiency virus type 1/type 2 reverse transcriptases display reversed sensitivity to nonnucleoside analog inhibitors. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9878–9882. doi: 10.1073/pnas.88.21.9878. [DOI] [PMC free article] [PubMed] [Google Scholar]