Physiologically-Based Pharmacokinetic Modeling Approach to Predict Rifampin-Mediated Intestinal P-Glycoprotein Induction.

Autor: Yamazaki S; Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development, San Diego, California, USA., Costales C; Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development, Groton, Connecticut, USA., Lazzaro S; Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development, Groton, Connecticut, USA., Eatemadpour S; Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development, Groton, Connecticut, USA., Kimoto E; Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development, Groton, Connecticut, USA., Varma MV; Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development, Groton, Connecticut, USA.
Jazyk: angličtina
Zdroj: CPT: pharmacometrics & systems pharmacology [CPT Pharmacometrics Syst Pharmacol] 2019 Sep; Vol. 8 (9), pp. 634-642. Date of Electronic Publication: 2019 Sep 05.
DOI: 10.1002/psp4.12458
Abstrakt: Physiologically-based pharmacokinetic (PBPK) modeling is a powerful tool to quantitatively describe drug disposition profiles in vivo, thereby providing an alternative to predict drug-drug interactions (DDIs) that have not been tested clinically. This study aimed to predict effects of rifampin-mediated intestinal P-glycoprotein (Pgp) induction on pharmacokinetics of Pgp substrates via PBPK modeling. First, we selected four Pgp substrates (digoxin, talinolol, quinidine, and dabigatran etexilate) to derive in vitro to in vivo scaling factors for intestinal Pgp kinetics. Assuming unbound Michaelis-Menten constant (K m ) to be intrinsic, we focused on the scaling factors for maximal efflux rate (J max ) to adequately recover clinically observed results. Next, we predicted rifampin-mediated fold increases in intestinal Pgp abundances to reasonably recover clinically observed DDI results. The modeling results suggested that threefold to fourfold increases in intestinal Pgp abundances could sufficiently reproduce the DDI results of these Pgp substrates with rifampin. Hence, the obtained fold increases can potentially be applicable to DDI prediction with other Pgp substrates.
(© 2019 Pfizeh Inc CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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