| Autor: |
Veronese, Laurence, Rautaureau, Jacques, Sadler, Brian M., Gillotin, Catherine, Petite, Jean-Pierre, Pillegand, Bernard, Delvaux, Michel, Masliah, Claude, Fosse, Sandrine, Lou, Yu, Stein, Daniel S. |
| Zdroj: |
Antimicrobial Agents and Chemotherapy; April 2000, Vol. 44 Issue: 4 p821-826, 6p |
| Abstrakt: |
ABSTRACTAmprenavir (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 Emaxmodel, 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 α1-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. |
| Databáze: |
Supplemental Index |
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