Single-dose pharmacokinetics of amprenavir, a human immunodeficiency virus type 1 protease inhibitor, in subjects with normal or impaired hepatic function.
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.
Veronese
L
L
Laboratoire Glaxo Wellcome, 78163 Marly-le-Roi, France. lv48262@glaxowellcome.co.uk
Rautaureau
J
J
Sadler
B M
BM
Gillotin
C
C
Petite
J P
JP
Pillegand
B
B
Delvaux
M
M
Masliah
C
C
Fosse
S
S
Lou
Y
Y
Stein
D S
DS
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*
D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; C095108:amprenavir