Hepatic Impairment and the Differential Effects on Drug Clearance Mechanisms: Analysis of Pharmacokinetic Changes in Disease State.

Abstract

Liver dysfunction can impact drug disposition and may lead to altered pharmacokinetics (PK). Here, we characterized the modulation in the in vivo activity of drug metabolizing enzymes and membrane transporters in populations with varying degrees of hepatic impairment (HI). Analysis of a well-curated dataset of 357 drugs across a range of clearance mechanisms suggested that the PK of OATP1B substrates is markedly altered by HI, while changes associated with other clearance mechanisms are relatively small. Of the metabolizing enzymes, CYP1A2 and UGTs were found to be most sensitive to disease progression, while PK changes of CYP2C/CYP2D6/CYP3A substrates were relatively less impacted. The median estimated loss in OATP1B and CYP3A activities, after adjusting for alterations in plasma protein binding, was found to be about 90% (n = 18) and 57% (n = 53) in severe HI, compared to healthy control, respectively. Large variability of AUC change within each HI category was present for CYP3A substrates compared to OATP1B substrates. Interestingly, exposure of drugs secreted in bile was not affected, while a statistically significant (P < 0.001) increase in AUC was noted for renally cleared drugs in severe HI. For CYP3A substrates, linear relationships (P < 0.001) between disease-induced AUC changes and AUC changes perpetrated by CYP3A probe inhibitor (ketoconazole/itraconazole) and the hepatic extraction ratio were evident. Similarly, there was a significant correlation between AUC changes following OATP1B inhibitor (rifampicin) and in the disease state for OATP1B substrates. Collectively, this meta-analysis suggests differential modulation in various clearance mechanisms and provides quantitation of the progressive reduction in metabolic/transport activity in HI.