title: Single-dose pharmacokinetics of amprenavir, a human immunodeficiency virus type 1 protease inhibitor, in subjects with normal or impaired hepatic function.
abstract: Amprenavir (141W94) is extensively metabolized by P450 cytochromes, specifically, CYP3A4. Because hepatic insufficiency reduces P450-mediated metabolism, the concentrations in plasma of drugs metabolized through this pathway are often increased in subjects with liver disease. Following administration of a single, oral dose of 600 mg of amprenavir, pharmacokinetic parameters were determined for 10 subjects with severe cirrhosis, 10 subjects with moderate cirrhosis, and 10 healthy volunteers. Model-independent methods for determining the area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC(0-infinity)) showed an increase in amprenavir AUC(0-infinity) of 2.5-fold in the group with moderate cirrhosis and 4.5-fold in the group with severe cirrhosis compared with that in the control group of healthy volunteers (P < 0.05). AUC(0-infinity) was linearly related to the severity of liver disease, as assessed by the Child-Pugh score. Of the laboratory data used to calculate the Child-Pugh score, only the mean total bilirubin concentration showed a significant relationship with AUC(0-infinity). The relationship between the total bilirubin concentration and the AUC(0-infinity) of amprenavir was well characterized by a simple E(max) model, suggesting that the total bilirubin concentration may be a useful parameter for predicting the amprenavir AUC in subjects with hepatic insufficiency. Finally, the sera of cirrhotic subjects showed significant decreases in the levels of alpha(1)-acid glycoprotein, the primary plasma binding protein for amprenavir. On the basis of the results of this study, for an exposure equivalent to a clinical dose of 1,200 mg twice daily in subjects without cirrhosis, subjects with Child-Pugh scores of 5 to 8 should receive a twice-daily 450-mg dose of amprenavir, and subjects with Child-Pugh scores of 9 to 15 should receive a twice-daily 300-mg dose of amprenavir.
authors.affiliation: Laboratoire Glaxo Wellcome, 78163 Marly-le-Roi, France. lv48262@glaxowellcome.co.uk
authors.forename: L
authors.initials: L
authors.lastname: Veronese
authors.forename: J
authors.initials: J
authors.lastname: Rautaureau
authors.forename: B M
authors.initials: BM
authors.lastname: Sadler
authors.forename: C
authors.initials: C
authors.lastname: Gillotin
authors.forename: J P
authors.initials: JP
authors.lastname: Petite
authors.forename: B
authors.initials: B
authors.lastname: Pillegand
authors.forename: M
authors.initials: M
authors.lastname: Delvaux
authors.forename: C
authors.initials: C
authors.lastname: Masliah
authors.forename: S
authors.initials: S
authors.lastname: Fosse
authors.forename: Y
authors.initials: Y
authors.lastname: Lou
authors.forename: D S
authors.initials: DS
authors.lastname: Stein
mesh_terms: D000328:Adult; D019540:Area Under Curve; D002219:Carbamates; D005260:Female; D005663:Furans; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D013449:Sulfonamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; C095108:amprenavir