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Pharmacokinetics of R 82913 in AIDS patients: a phase I dose-finding study of oral administration compared with intravenous infusion.

Abstract
The pharmacokinetics of oral administration of R 82913, or tetrahydroimidazol [4,5,1-jk]-benzodiazepin-2(1H)-one or -thione (TIBO), was compared with those of intravenous administration in five AIDS patients. TIBO was administered as a single daily 1-h infusion of 100 mg for 29 days and orally as a single daily dose for 14 days with three consecutive regimens of 100, 200, and 100 mg with probenecid (1 g) daily. Each cycle was followed by a wash-out period. Oral bioavailability of TIBO appears to be low and is not improved by the adjunction of probenecid. Trough levels obtained with oral administration systematically remained far below the 90% inhibitory concentration of TIBO against human immunodeficiency virus type 1 (HIV-1). Tolerance of TIBO was excellent. No clinical efficacy could be demonstrated. p24 antigenemia decreased significantly in one patient under intravenous therapy. TIBO derivatives are promising anti-HIV-1 agents in vitro, but improvement of oral bioavailability is needed before implementation of long-term efficacy and tolerability studies. Moreover, rapid emergence of resistance, which has been recently documented, constitutes a major problem with most nonnucleoside reverse transcriptase inhibitors.
AuthorsS De Wit, P Hermans, B Sommereijns, E O'Doherty, R Westenborghs, V van de Velde, G F Cauwenbergh, N Clumeck
JournalAntimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 36 Issue 12 Pg. 2661-3 (Dec 1992) ISSN: 0066-4804 [Print] United States
PMID1482134 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Comparative Study, Controlled Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antiviral Agents
  • Imidazoles
  • Benzodiazepines
  • R-82913
Topics
  • Acquired Immunodeficiency Syndrome (drug therapy, metabolism)
  • Administration, Oral
  • Adult
  • Antiviral Agents (administration & dosage, adverse effects, pharmacokinetics)
  • Benzodiazepines (administration & dosage, adverse effects, pharmacokinetics)
  • Drug Administration Schedule
  • Humans
  • Imidazoles (administration & dosage, adverse effects, pharmacokinetics)
  • Infusions, Intravenous
  • Male
  • Prospective Studies

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