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JAC Advance Access originally published online on May 18, 2004
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Journal of Antimicrobial Chemotherapy 2004 54(1):206-210; doi:10.1093/jac/dkh252
JAC vol.54 no.1 © The British Society for Antimicrobial Chemotherapy 2004; all rights reserved.

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

Ulrik S. Justesen1,*, Niels A. Klitgaard2, Kim Brosen1 and Court Pedersen3

1 Institute of Public Health, Clinical Pharmacology, University of Southern Denmark, Winsloewparken 19, DK-5000 Odense C; 2 Department of Clinical Biochemistry, Odense University Hospital; 3 Department of Infectious Diseases, Odense University Hospital, Odense, Denmark

* Corresponding author. Tel: +45-6550-3759; Fax: +45-6591-6089; Email: ujustesen{at}health.sdu.dk

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


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