AEGiS-08IAC: A phase I multiple dose study of U-87,201E, a non-nucleoside RT inhibitor, in normal healthy males.

8th International AIDS Conference


Amsterdam, Netherlands — July 19-24, 1992

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A phase I multiple dose study of U-87,201E, a non-nucleoside RT inhibitor, in normal healthy males.

Int Conf AIDS 1992 Jul 19-24; 8:We47 (abstract no. WeB 1015)
Cox SR, Batts DH, Dietz AJ, Hanover C, Peel BG, Elfring GL, Staton BA; Upjohn Company, Kalamazoo, MI.

OBJECTIVES: U-87,201E is a non-nucleoside RT inhibitor which was well tolerated when administered to both normal healthy males and asymptomatic HIV+ patients in single oral doses up to 1,600mg. This study was performed to evaluate the safety, tolerability, and pharmacokinetics of U-87,201E in normal healthy males following oral doses of 200, 400, or 600mg every six hours for 7 1/2 days.

METHODS: Randomized, double-blind, placebo-controlled, escalating dose study with two placebo recipients and six active drug recipients per dose level.

RESULTS: U-87,201E was well tolerated at the two lowest doses. Reversible elevations in serum bilirubin (maximum 3.1mg/dl) occurred by day 8 in 2/2 pioneers in the 600mg dose group, and no further subjects were enrolled. Serum concentrations of U-87,201E from the last dosing interval are listed below: TABULAR DATA, SEE ABSTRACT VOLUME. Steady-state pharmacokinetics of U-87,201E were apparently not achieved by day 7 in several subjects. Serum concentration data for the N-dealkyl metabolite of U-87,201E suggest that the formation clearance of this metabolite is nonlinear.

CONCLUSIONS: Oral U-87,201E was tolerated for one week at doses of 200 or 400mg every 6 hours. The nonlinear pharmacokinetics of U-87,201E following multiple doses were not predicted from the single dose studies. Toxicity to U-87,201E appears to be related to trough serum drug concentrations greater than 30 microM.

Keywords: AEGIS, Area Under Curve, Double-Blind Method, Biological Availability, Metabolic Clearance Rate, Pharmaceutical Preparations, Tablets, Human, Male, antagonists & inhibitors, pharmacokinetics, ICA8KWDaegis,areaundercurve,double-blindmethod,biologicalavailability,metabolicclearancerate,pharmaceuticalpreparations,tablets,human,male,antagonists&inhibitors,pharmacokinetics,ica8
920719
WeB1015

Copyright © 1992 - International AIDS Society (IAS). Reproduction of this abstract (other than one copy for personal reference) must be cleared through the IAS.