Quantitative Estimation of Plasma Free Drug Fraction in Patients With Varying Degrees of Hepatic Impairment: A Methodological Evaluation

• Published in: Journal of pharmaceutical sciences 2018-07, Vol.107 (7), p.1948-1956
• Main Authors: Li, Guo-Fu, Yu, Guo, Li, Yanfei, Zheng, Yi, Zheng, Qing-Shan, Derendorf, Hartmut
• Format: Article
• Language: English
• Subjects: albumin; alpha 1-acid glycoprotein; clinical pharmacokinetics; fraction unbound; hepatic impairment; physiologically based pharmacokinetics; plasma protein binding
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1016/j.xphs.2018.02.021

Quantitative prediction of unbound drug fraction (fu) is essential for scaling pharmacokinetics through physiologically based approaches. However, few attempts have been made to evaluate the projection of fu values under pathological conditions. The primary objective of this study was to predict fu values (n = 105) of 56 compounds with or without the information of predominant binding protein in patients with varying degrees of hepatic insufficiency by accounting for quantitative changes in molar concentrations of either the major binding protein or albumin plus alpha 1-acid glycoprotein associated with differing levels of hepatic dysfunction. For the purpose of scaling, data pertaining to albumin and α1-acid glycoprotein levels in response to differing degrees of hepatic impairment were systematically collected from 919 adult donors. The results of the present study demonstrate for the first time the feasibility of physiologically based scaling fu in hepatic dysfunction after verifying with experimentally measured data of a wide variety of compounds from individuals with varying degrees of hepatic insufficiency. Furthermore, the high level of predictive accuracy indicates that the inter-relation between the severity of hepatic impairment and these plasma protein levels are physiologically accurate. The present study enhances the confidence in predicting fu in hepatic insufficiency, particularly for albumin-bound drugs.