Usage of In Vitro Metabolism Data for Drug‐Drug Interaction in Physiologically Based Pharmacokinetic Analysis Submissions to the US Food and Drug Administration

2021 ◽  
Author(s):  
Jieon Lee ◽  
Yuching Yang ◽  
Xinyuan Zhang ◽  
Jianghong Fan ◽  
Manuela Grimstein ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Drug Administration ◽  
Food And Drug Administration ◽  
In Vitro Metabolism ◽  
Pharmacokinetic Analysis ◽  
Physiologically Based Pharmacokinetic ◽  
The Us ◽  
Physiologically Based ◽  
Drug Drug Interaction

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model was established in PK-Sim®, using 45 clinical studies (dosing range 0.1–250 mg), including literature as well as unpublished Boehringer Ingelheim data.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

scholarly journals In vitro and physiologically‐based pharmacokinetic based assessment of drug–drug interaction potential of canagliflozin

2016 ◽  
Vol 83 (5) ◽  
pp. 1082-1096 ◽  
Author(s):  
Rao N. V. S. Mamidi ◽  
Shannon Dallas ◽  
Carlo Sensenhauser ◽  
Heng Keang Lim ◽  
Ellen Scheers ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Interaction Potential ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based ◽  
Drug Drug Interaction

scholarly journals Evaluation for Potential Drug–Drug Interaction of MT921 Using In Vitro Studies and Physiologically–Based Pharmacokinetic Models

2021 ◽  
Vol 14 (7) ◽  
pp. 654
Author(s):  
Hyo-jeong Ryu ◽  
Hyun-ki Moon ◽  
Junho Lee ◽  
Gi-hyeok Yang ◽  
Sung-yoon Yang ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Bile Acid ◽  
Pbpk Model ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Physiologically Based Pharmacokinetic ◽  
Anion Transporter ◽  
Physiologically Based ◽  
Drug Drug Interaction

MT921 is a new injectable drug developed by Medytox Inc. to reduce submental fat. Cholic acid is the active pharmaceutical ingredient, a primary bile acid biosynthesized from cholesterol, endogenously produced by liver in humans and other mammals. Although individuals treated with MT921 could be administered with multiple medications, such as those for hypertension, diabetes, and hyperlipidemia, the pharmacokinetic drug–drug interaction (DDI) has not been investigated yet. Therefore, we studied in vitro against drug-metabolizing enzymes and transporters. Moreover, we predicted the potential DDI between MT921 and drugs for chronic diseases using physiologically-based pharmacokinetic (PBPK) modeling and simulation. The magnitude of DDI was found to be negligible in in vitro inhibition and induction of cytochrome P450s and UDP-glucuronosyltransferases. Organic anion transporting polypeptide (OATP)1B3, organic anion transporter (OAT)3, Na+-taurocholate cotransporting polypeptide (NTCP), and apical sodium-dependent bile acid transporter (ASBT) are mainly involved in MT921 transport. Based on the result of in vitro experiments, the PBPK model of MT921 was developed and evaluated by clinical data. Furthermore, the PBPK model of amlodipine was developed and evaluated. PBPK DDI simulation results indicated that the pharmacokinetics of MT921 was not affected by the perpetrator drugs. In conclusion, MT921 could be administered without a DDI risk based on in vitro study and related in silico simulation. Further clinical studies are needed to validate this finding.

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