Dose-dependent pharmacokinetics of delavirdine in combination with amprenavir in healthy volunteers.
OBJECTIVE
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.
Justesen
Ulrik S
US
Institute of Public Health, Clinical Pharmacology, University of Southern Denmark, Winsloewparken 19, DK-5000 Odense C, Denmark. ujustesen@health.sdu.dk
Klitgaard
Niels A
NA
Brosen
Kim
K
Pedersen
Court
C
D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002219:Carbamates; D002851:Chromatography, High Pressure Liquid; D020008:Delavirdine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005663:Furans; D006801:Humans; D008297:Male; D011446:Prospective Studies; D013056:Spectrophotometry, Ultraviolet; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
D019380:Anti-HIV Agents; D002219:Carbamates; D004338:Drug Combinations; D005663:Furans; D013449:Sulfonamides; C095108:amprenavir; D020008:Delavirdine