http://orcid.org/0000-0002-1068-4261
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Abstract
Pharmacokinetic profiles of pemafibrate with virtual drug and/or disease interactions were assessed by creating a detailed physiologically based pharmacokinetic (PBPK) model.
Passive diffusion clearance in liver was experimentally determined as 0.013 mL/min/106 human hepatocytes. In vitro intrinsic clearance values for pemafibrate by cytochromes P450 2C8, 2C9, and 3A4 were 54, 26, and 16 μL/min/mg protein, respectively. Values for the effective permeability and the intrinsic clearance of hepatic uptake by organic anion transporting polypeptide (OATP) 1B1 were optimized in a simulator platform.
This PBPK model was subsequently validated using reported maximum pemafibrate plasma concentration and area under the curve values in reported interaction studies in healthy subjects co-administered with rifampicin.
For subjects with Child-Pugh A and B liver cirrhosis, the intrinsic clearance of hepatic uptake of pemafibrate by OATP1B1 were modeled using 53% and 31% of that of healthy subjects, respectively. Virtual co-administrations of rifampicin and sacubitril (OATP1B inhibitors) in subjects with renal impairment and liver cirrhosis resulted in 11- to 13-folds (rifampicin) and 1.1- to 1.3-folds (sacubitril) increased plasma exposures of pemafibrate.
The current PBPK model and simulations revealed different pharmacokinetic profiles for pemafibrate following co-administration of rifampicin or sacubitril in virtual subjects with or without renal/hepatic impairment.
Acknowledgments
The authors are grateful to Yoshihiko Tsunenari and Hiroyuki Kawai for their support. The authors also thank David Smallbones for copyediting a draft of this article.
Disclosure statement
The authors declare that there are no conflicts of interest.