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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-
) showed an increase in amprenavir
AUC0-
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-
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-
. The relationship between the total bilirubin concentration and the AUC0-
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
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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