TY - JOUR T1 - Scaling Factors for Clearance in Adult Liver Cirrhosis JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1271 LP - 1282 DO - 10.1124/dmd.120.000152 VL - 48 IS - 12 AU - Eman El-Khateeb AU - Brahim Achour AU - Daniel Scotcher AU - Zubida M. Al-Majdoub AU - Varinder Athwal AU - Jill Barber AU - Amin Rostami-Hodjegan Y1 - 2020/12/01 UR - http://dmd.aspetjournals.org/content/48/12/1271.abstract N2 - In vitro to 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 biologic 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 noncirrhotic and 32 cirrhotic livers (six 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 were 88.2, 67.9, 62.2, and 75.4 (mg⋅g−1) for mild, moderate, and severe cirrhosis and control livers, respectively, with statistically lower values for severe versus 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 alfentanil, 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.SIGNIFICANCE STATEMENT Cirrhosis-specific scalars required for extrapolation from microsomal or cytosolic in vitro systems to liver tissue are lacking. These scalars can help in predicting drug clearance and selection of dosage regimens for cirrhosis populations. Attempts to consider potential changes have been empirical and ignored the potential impact of the cause of cirrhosis. We obtained experimental values for these scalars for the first time and assessed their impact on predicted exposure to various substrate drugs using physiologically-based pharmacokinetics simulations. ER -