title: Dose-dependent pharmacokinetics of delavirdine in combination with amprenavir in healthy volunteers.
abstract: 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.
authors.affiliation: Institute of Public Health, Clinical Pharmacology, University of Southern Denmark, Winsloewparken 19, DK-5000 Odense C, Denmark. ujustesen@health.sdu.dk
authors.forename: Ulrik S
authors.initials: US
authors.lastname: Justesen
authors.forename: Niels A
authors.initials: NA
authors.lastname: Klitgaard
authors.forename: Kim
authors.initials: K
authors.lastname: Brosen
authors.forename: Court
authors.initials: C
authors.lastname: Pedersen
mesh_terms: 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*
chemical_list: D019380:Anti-HIV Agents; D002219:Carbamates; D004338:Drug Combinations; D005663:Furans; D013449:Sulfonamides; C095108:amprenavir; D020008:Delavirdine