Journal Article

Dose-dependent pharmacokinetics of delavirdine in combination with amprenavir in healthy volunteers

Ulrik S. Justesen, Niels A. Klitgaard, Kim Brosen and Court Pedersen

in Journal of Antimicrobial Chemotherapy

Published on behalf of British Society for Antimicrobial Chemotherapy

Volume 54, issue 1, pages 206-210
Published in print July 2004 | ISSN: 0305-7453
Published online July 2004 | e-ISSN: 1460-2091 | DOI: http://dx.doi.org/10.1093/jac/dkh252
Dose-dependent pharmacokinetics of delavirdine in combination with amprenavir in healthy volunteers

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  • Medical Oncology
  • Critical Care

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Objectives: To investigate different dose combinations of amprenavir and delavirdine in order to assess an optimal dose suitable for clinical use.

Methods: This was a prospective, open-label, controlled, three-period, multiple-dose study with nine healthy volunteers. The volunteers received three different dose combinations of amprenavir and delavirdine twice a day for 10 days with a subsequent 12 h pharmacokinetic evaluation. Combination 1: amprenavir 600 mg and delavirdine 600 mg; combination 2: amprenavir 600 mg and delavirdine 800 mg; combination 3: amprenavir 450 mg and delavirdine 1000 mg. The combinations were taken at least 2 weeks apart.

Results: Differences in median delavirdine Cmax, C12 and AUC0–12 were seen when comparing the three combinations (3 > 2>1) (P<0.04). A considerable and clinically important higher median C12 was seen with combination 3 when compared to combination 1 (835 to 3944 ng/mL) (P=0.0039). Only small differences in the amprenavir pharmacokinetic parameters were seen between the three dose combinations, with a median C12 of 412, 434 and 536 ng/mL, respectively.

Conclusions: In this study, an increase of 472% in median delavirdine C12 was seen with a delavirdine dose increase of only 67% (600 to 1000 mg). Saturation of the CYP3A4 enzymes and/or possibly also P-glycoprotein could be involved. Combination 3 was considered most suitable for clinical use, but because of the large inter-individual variation in steady-state concentrations, the use of the combination should be supported by therapeutic drug monitoring and restricted to certain patients.

Keywords: interactions; protease inhibitors; reverse transcriptase inhibitors

Journal Article.  3445 words.  Illustrated.

Subjects: Medical Oncology ; Critical Care

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