Reduced Physiologically-Based Pharmacokinetic Model of Repaglinide: Impact of OATP1B1 and CYP2C8 Genotype and Source of In Vitro Data on the Prediction of Drug-Drug Interaction Risk

2014 ◽  
Vol 31 (9) ◽  
pp. 2367-2382 ◽  
Author(s):  
Michael Gertz ◽  
Nikolaos Tsamandouras ◽  
Carolina Säll ◽  
J. Brian Houston ◽  
Aleksandra Galetin
Keyword(s):  
Drug Interaction ◽  
Pharmacokinetic Model ◽  
Physiologically Based Pharmacokinetic Model ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based ◽  
Drug Drug Interaction ◽  
Vitro Data ◽  
In Vitro Data

scholarly journals A Mechanistic, Enantioselective, Physiologically Based Pharmacokinetic Model of Verapamil and Norverapamil, Built and Evaluated for Drug–Drug Interaction Studies

Pharmaceutics ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 556 ◽  
Author(s):  
Nina Hanke ◽  
Denise Türk ◽  
Dominik Selzer ◽  
Sabrina Wiebe ◽  
Éric Fernandez ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Pharmacokinetic Model ◽  
Competitive Inhibition ◽  
Open Systems ◽  
Whole Body ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based ◽  
Drug Drug Interaction ◽  
Enantioselective Metabolism

The calcium channel blocker and antiarrhythmic agent verapamil is recommended by the FDA for drug–drug interaction (DDI) studies as a moderate clinical CYP3A4 index inhibitor and as a clinical Pgp inhibitor. The purpose of the presented work was to develop a mechanistic whole-body physiologically based pharmacokinetic (PBPK) model to investigate and predict DDIs with verapamil. The model was established in PK-Sim®, using 45 clinical studies (dosing range 0.1–250 mg), including literature as well as unpublished Boehringer Ingelheim data. The verapamil R- and S-enantiomers and their main metabolites R- and S-norverapamil are represented in the model. The processes implemented to describe the pharmacokinetics of verapamil and norverapamil include enantioselective plasma protein binding, enantioselective metabolism by CYP3A4, non-stereospecific Pgp transport, and passive glomerular filtration. To describe the auto-inhibitory and DDI potential, mechanism-based inactivation of CYP3A4 and non-competitive inhibition of Pgp by the verapamil and norverapamil enantiomers were incorporated based on in vitro literature. The resulting DDI performance was demonstrated by prediction of DDIs with midazolam, digoxin, rifampicin, and cimetidine, with 21/22 predicted DDI AUC ratios or Ctrough ratios within 1.5-fold of the observed values. The thoroughly built and qualified model will be freely available in the Open Systems Pharmacology model repository to support model-informed drug discovery and development.

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