Predicting the effect of hepatic disease on systemic drug exposure

The purpose of this study was to employ a comprehensive Top-Down scaling approach to estimate the impact of alterations in bioavailability (gut wall (F_G) and hepatic first pass (F_H,)) and clearance pathways (renal (Cl_R) and hepatic (Cl_H)) on the relative changes to drug exposure (AUCR, area under the curve ratio in liver disease compared to otherwise healthy patients). Observations evaluating drug clearance as a function of Child-Pugh (C-P) categories (mild, moderate, and severe) for hepatically cleared drugs (f_e <0.3) were obtained from literature sources. The analysis consisted of 319 AUCR observations across 127 unique drugs. Top-down analysis was used to account for changes in F_G, F_H, Cl_R, and Cl_H using information regarding specific CYP pathways (f_m) and available pharmacokinetic parameters, as well as additional scaling approaches for renal function, CYP activity, shunting, and other factors. In several data cuts, the Top-Down scaling approach provided reasonable estimates of the effect of liver disease. Analysis of a dataset of 77 data points (48 drugs) with observed AUCR values exceeding 2 in patients with severe liver disease, revealed that these drugs were predominantly CYP3А4 substrates. Studies with complete data sets for multiple C-P categories provided greater insights into drug risk in liver disease, especially for identifying drugs with AUCR>2 in severe liver disease. The Top-Down scaling approach was comparable to bottom-up methods (PBPK) in predicting the relative changes to drug exposure (AUCR) for various degrees of liver disease based on C-P categories. Furthermore, this approach was able to highlight the key criteria for drugs with the highest risk of increased exposure (AUCR>2) in liver disease. These drugs are primarily eliminated via hepatic metabolism (f_e < 0.5), and their clearance pathways include either one (or a combination) of CYP1A2, CYP2C19, CYP2D6, and CYP3A4. Oral administration significantly increases the risk of increased exposures, particularly those with substantial hepatic and gut wall first-pass (F_H and F_G) metabolism.