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Pharmacokinetics of a Second-Generation NNRTI, DPC 083, after Multiple Oral Doses in Healthy Volunteers W. D. FISKE*, J. M. BRENNAN, R. R. HARRISON, J. L. JOBES, M. L. VOLPATO, and S. G. GRIFFITH.
DuPont Pharmaceuticals Co., Newark, NJ, and Wilmington, DE Background and Objective: DPC 083 is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. DPC 083 is potent against the single mutant variants such as L100I and K103N, and against double substitution variants such as K103N + Y181C, K103N + V108I and K103N + P225H which are observed in nevirapine, delavirdine and efavirenz failures. In this study, the pharmacokinetics of DPC 083 were evaluated after multiple daily doses of DPC 083.
Method: Five cohorts of male subjects (6 active/2 placebo per cohort) received 50, 100, 200, 300 and 400 mg doses of DPC 083 and one cohort of female subjects received 100 mg doses of DPC 083. Two doses were administered on the first day, followed by single daily doses for the following 8 days, for a total of 10 doses. Plasma samples were collected during the dosing period and for 3 weeks thereafter.
Results: After multiple once-daily doses, peak plasma concentrations of DPC 083 were achieved 2.5 to 4 hours after dosing. Peak to trough changes were small (ratio of approximately 1.3). DPC 083 had a very long terminal half-life (>140 hours). DPC 083 plasma concentrations increased during the dosing period, and steady-state had not been achieved after 10 doses. After 10 doses of >100 mg DPC 083, the average trough concentration (C24) exceeded the calculated protein-binding-adjusted concentration needed for 90% inhibition of wild type viruses by >172-fold, of K103N virus by >11-fold, of K103N + P225H by >1.9-fold, or K103N + V108I by >2.9-fold, and of K103N + Y181C by >1.6-fold.
Conclusion: DPC 083, administered once-daily, provided plasma levels that are predicted to be in excess of those required for 90% inhibition of wild type, K103N, and several clinically important double mutant viruses, including those seen in patients failing current NNRTI combination therapy.
Key Words: DPC 083, NNRTI, Pharmacokinetics
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