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Antimicrobial Agents and Chemotherapy, April 2000, p. 821-826, Vol. 44, No. 4
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Single-Dose Pharmacokinetics of Amprenavir, a Human Immunodeficiency Virus Type 1 Protease Inhibitor, in Subjects with Normal or Impaired Hepatic Function

Laurence Veronese,1,* Jacques Rautaureau,2 Brian M. Sadler,3 Catherine Gillotin,1 Jean-Pierre Petite,4 Bernard Pillegand,5 Michel Delvaux,6 Claude Masliah,7 Sandrine Fosse,1 Yu Lou,3 and Daniel S. Stein3

Laboratoire Glaxo Wellcome, 78163 Marly-le-Roi,1 Hôpital Avicenne, 93000 Bobigny,2 Hôpital Broussais, 75015 Paris,4 Hôpital Dupuytren, 87042 Limoges,5 Hôpital de Rangueil, 31400 Toulouse,6 and Hôtel-Dieu, 44035 Nantes,7 France, and Glaxo Wellcome, Inc., Research Triangle Park, North Carolina3

Received 9 April 1999/Returned for modification 23 October 1999/Accepted 27 December 1999

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 (AUC0-infinity ) showed an increase in amprenavir AUC0-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). AUC0-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 AUC0-infinity . The relationship between the total bilirubin concentration and the AUC0-infinity of amprenavir was well characterized by a simple Emax 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.

* Corresponding author. Mailing address: Department of Clinical Pharmacology, Laboratoire Glaxo Wellcome, 78163 Marly-le-Roi, France. E-mail: lv48262{at}glaxowellcome.co.uk.

Antimicrobial Agents and Chemotherapy, April 2000, p. 821-826, Vol. 44, No. 4
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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