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A Mechanistic, Enantioselective, Physiologically Based Pharmacokinetic Model of Verapamil and Norverapamil, Built and Evaluated for Drug-Drug Interaction Studies.
Pharmaceutics. 2020 Jun 16; 12(6)P

Abstract

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model was established in PK-Sim®, using 45 clinical studies (dosing range 0.1-250 mg), including literature as well as unpublished Boehringer Ingelheim data.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.

Authors+Show Affiliations

Clinical Pharmacy, Saarland University, 66123 Saarbrücken, Germany.Clinical Pharmacy, Saarland University, 66123 Saarbrücken, Germany.Clinical Pharmacy, Saarland University, 66123 Saarbrücken, Germany.Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach, Germany. Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, 69120 Heidelberg, Germany.Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach, Germany.Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach, Germany.Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach, Germany.Clinical Pharmacy, Saarland University, 66123 Saarbrücken, Germany.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32560124

Citation

Hanke, Nina, et al. "A Mechanistic, Enantioselective, Physiologically Based Pharmacokinetic Model of Verapamil and Norverapamil, Built and Evaluated for Drug-Drug Interaction Studies." Pharmaceutics, vol. 12, no. 6, 2020.
Hanke N, Türk D, Selzer D, et al. A Mechanistic, Enantioselective, Physiologically Based Pharmacokinetic Model of Verapamil and Norverapamil, Built and Evaluated for Drug-Drug Interaction Studies. Pharmaceutics. 2020;12(6).
Hanke, N., Türk, D., Selzer, D., Wiebe, S., Fernandez, É., Stopfer, P., Nock, V., & Lehr, T. (2020). A Mechanistic, Enantioselective, Physiologically Based Pharmacokinetic Model of Verapamil and Norverapamil, Built and Evaluated for Drug-Drug Interaction Studies. Pharmaceutics, 12(6). https://doi.org/10.3390/pharmaceutics12060556
Hanke N, et al. A Mechanistic, Enantioselective, Physiologically Based Pharmacokinetic Model of Verapamil and Norverapamil, Built and Evaluated for Drug-Drug Interaction Studies. Pharmaceutics. 2020 Jun 16;12(6) PubMed PMID: 32560124.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A Mechanistic, Enantioselective, Physiologically Based Pharmacokinetic Model of Verapamil and Norverapamil, Built and Evaluated for Drug-Drug Interaction Studies. AU - Hanke,Nina, AU - Türk,Denise, AU - Selzer,Dominik, AU - Wiebe,Sabrina, AU - Fernandez,Éric, AU - Stopfer,Peter, AU - Nock,Valerie, AU - Lehr,Thorsten, Y1 - 2020/06/16/ PY - 2020/05/15/received PY - 2020/06/08/revised PY - 2020/06/09/accepted PY - 2020/6/21/entrez PY - 2020/6/21/pubmed PY - 2020/6/21/medline KW - P-glycoprotein (Pgp) KW - cytochrome P450 3A4 (CYP3A4) KW - drug–drug interactions (DDIs) KW - mechanism-based inactivation (MBI) KW - model-informed drug discovery and development (MID3) KW - non-competitive inhibition KW - norverapamil KW - physiologically based pharmacokinetic (PBPK) modeling KW - verapamil JF - Pharmaceutics JO - Pharmaceutics VL - 12 IS - 6 N2 - 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. SN - 1999-4923 UR - https://www.unboundmedicine.com/medline/citation/32560124/A_Mechanistic,_Enantioselective,_Physiologically_Based_Pharmacokinetic_Model_of_Verapamil_and_Norverapamil,_Built_and_Evaluated_for_Drug-Drug_Interaction_Studies L2 - https://www.mdpi.com/resolver?pii=pharmaceutics12060556 DB - PRIME DP - Unbound Medicine ER -
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