Pharmacokinetic study of human immunodeficiency virus protease inhibitors used in combination with amprenavir.
In an open-label, randomized, multicenter, multiple-dose pharmacokinetic study, we determined the steady-state pharmacokinetics of amprenavir with and without coadministration of indinavir, nelfinavir, or saquinavir soft gel formulation in 31 human immunodeficiency virus type 1-infected subjects. The results indicated that amprenavir plasma concentrations were decreased by saquinavir soft gel capsule (by 32% for area under the concentration-time curve at steady state [AUC(ss)] and 37% for peak plasma concentration at steady state [C(max,ss)]) and increased by indinavir (33% for AUC(ss)). Nelfinavir significantly increased amprenavir minimum drug concentration at steady state (by 189%) but did not affect amprenavir AUC(ss) or C(max,ss). Nelfinavir and saquinavir steady-state pharmacokinetics were unchanged by coadministration with amprenavir compared with the historical monotherapy data. Concentrations of indinavir, coadministered with amprenavir, in plasma decreased in both single-dose and steady-state evaluations. The changes in amprenavir steady-state pharmacokinetic parameters, relative to those for amprenavir alone, were not consistent among protease inhibitors, nor were the changes consistent with potential interactions in CYP3A4 metabolism or P-glycoprotein transport. No dose adjustment of either protease inhibitor in any of the combinations studied is needed.
Sadler
B M
BM
Glaxo Wellcome (now GlaxoSmithKline) Inc., Research Triangle Park, North Carolina 27709-3398, USA.
Gillotin
C
C
Lou
Y
Y
Eron
J J
JJ
Lang
W
W
Haubrich
R
R
Stein
D S
DS
D000328:Adult; D019540:Area Under Curve; D018791:CD4 Lymphocyte Count; D002219:Carbamates; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D005663:Furans; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006679:HIV Seropositivity; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D019888:Nelfinavir / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D009961:Orosomucoid / Q000378:metabolism; D019258:Saquinavir / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
D002219:Carbamates; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005663:Furans; D017320:HIV Protease Inhibitors; D009961:Orosomucoid; D013449:Sulfonamides; C095108:amprenavir; D019469:Indinavir; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D019888:Nelfinavir; D019258:Saquinavir