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Drug metabolism and disposition: the biological fate of chemicals

Physiologically based pharmacokinetic prediction of telmisartan in human.


PMID 25092714

Abstract

A previously developed physiologically based pharmacokinetic model for hepatic transporter substrates was extended to an organic anion transporting polypeptide substrate, telmisartan. Predictions used in vitro data from sandwich culture human hepatocyte and human liver microsome assays. We have developed a novel method to calibrate partition coefficients (Kps) between nonliver tissues and plasma on the basis of published human positron emission tomography (PET) data to decrease the uncertainty in tissue distribution introduced by in silico-predicted Kps. With in vitro data-predicted hepatic clearances, published empirical scaling factors, and PET-calibrated Kps, the model could accurately recapitulate telmisartan pharmacokinetic (PK) behavior before 2.5 hours. Reasonable predictions also depend on having a model structure that can adequately describe the drug disposition pathways. We showed that the elimination phase (2.5-12 hours) of telmisartan PK could be more accurately recapitulated when enterohepatic recirculation of parent compound derived from intestinal deconjugation of glucuronide metabolite was incorporated into the model. This study demonstrated the usefulness of the previously proposed physiologically based modeling approach for purely predictive intravenous PK simulation and identified additional biologic processes that can be important in prediction.