Open AccessPrediction of the Pharmacokinetics of Pravastatin as an OATP Substrate Using Plateable Human Hepatocytes With Human Plasma Data and PBPK Modeling
Author(s) -
Mao Jialin,
Doshi Utkarsh,
Wright Matthew,
Hop Cornelis E. C. A.,
Li Albert P.,
Chen Yuan
Publication year - 2018
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12283
Subject(s) - physiologically based pharmacokinetic modelling , pravastatin , pharmacokinetics , transporter , chemistry , in vivo , human plasma , pharmacology , bioanalysis , organic anion transporting polypeptide , in vitro , chromatography , biochemistry , medicine , biology , microbiology and biotechnology , cholesterol , gene
Plateable human hepatocytes with human plasma were utilized to generate the uptake transporter kinetic data for pravastatin, an organic anion‐transporting polypeptide (OATP) transporter substrate. The active hepatic uptake of pravastatin was determined with a J max value of 134.4 pmol/min/million cells and K m of 76.77 µM in plateable human hepatocytes with human plasma. The physiologically‐based pharmacokinetic (PBPK) model with incorporation of these in vitro kinetic data successfully simulated the i.v. pharmacokinetic profile of pravastatin without applying scaling factor (the mean predicted area under the curve (AUC) is within 1.5‐fold of the observed). Furthermore, the PBPK model also adequately described the oral plasma concentration‐time profiles of pravastatin at different dose levels. The current investigation demonstrates an approach allowing us to build upon the translation of in vitro OATP uptake transporter data to in vivo , with a hope of utilizing the in vitro data for the prospective human pharmacokinetic (PK) prediction.