Extrapolations from Cirrhosis to Other Liver Diseases

Although liver disease is a heterogeneous group of diseases, the pharmacokinetics of a new drug is often limited to studies in cirrhotic patients. As this is the most common liver disease, this is of benefit for the

FIGURE 1 AUC of an antiinflammatory drug in patients with different degrees of liver function.

majority of patients. However, extrapolating to patients with other liver diseases may be difficult. Different kinds of liver diseases may affect the pharmacokinetics of a drug differently. For example cholestatic and noncholestatic cirrhosis appear to affect the enzyme expression and/or availability of specific enzymes in different ways [34, 35]. The amount of

FIGURE 2 Difference in AUC (%) in patients with liver impairment as compared with matched healthy volunteers vs. S-Albumin.

CYP1A2 appears to be decreased in both hepatocellular and cholestatic cirrhosis while the levels of CYP3A were only observed to decrease in patients with hepatocellular cirrhosis. The levels of CYP2E1 were reduced in patients with cholestatic cirrhosis while the decrease was seen at mRNA-but not protein-level in livers of patients with hepatocellular cirrhosis [34]. In contrast, markedly (5-10-fold) increases in CYP2E1 levels have been observed in alcoholics [36, 37]. Due to the discrepancies in effects of the different diseases, it is important to give information in the labeling regarding which population has been studied. If new markers of liver function are found, a safer and more precise extrapolation from cirrhosis to other diseases could be possible.

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