Scaling Factors for Clearance in Adult Liver Cirrhosis

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In-vitro in-vivo extrapolation (IVIVE) enables prediction of in vivo clinical outcomes related to drug exposure in various populations from in vitro data. Prudent IVIVE requires scalars specific to the biological characteristics of the system in each population. This study determined experimentally, for the first time, scalars in liver samples from patients with varying degrees of cirrhosis. Microsomal and cytosolic fractions were extracted from 13 non-cirrhotic and 32 cirrhotic livers (6 mild, 13 moderate, and 13 severe, based on Child-Pugh Score). Fractional protein content was determined and cytochrome P450 reductase activity was used to correct for microsomal protein loss. Although the median microsomal protein per gram liver (MPPGL) in mild, moderate, and severe cirrhosis (26.2, 32.4, and 30.8 mg.g-1, respectively) seemed lower than control livers (36.6 mg.g-1), differences were not statistically significant (Kruskal-Wallis test, p>0.05). Corresponding values for cytosolic protein per gram liver (CPPGL) were 88.2, 67.9, 62.2 and 75.4 (mg.g-1) for mild, moderate, sever cirrhosis and control livers, respectively, with statistically lower values for server vs controls (Mann-Whitney p=0.006). Cirrhosis associated with cancer showed lower MPPGL (24.8 mg.g-1) than cirrhosis associated with cholestasis (38.3 mg.g-1, p=0.003). Physiologically-based pharmacokinetic simulations with disease-specific scalars captured cirrhosis impact on exposure to afentanil, metoprolol, midazolam, and ethinylestradiol. These experimentally-determined scalars should alleviate the need for indirect scaling using functional liver volume. Scaling factors in cirrhosis might be a reflection of the etiology rather than the disease severity. Hence, bundling various cirrhotic conditions under the same umbrella when predicting hepatic impairment impact should be revisited.

Bibliographical metadata

Original languageEnglish
JournalDrug Metabolism and Disposition
Early online date25 Sep 2020
Publication statusE-pub ahead of print - 25 Sep 2020