Biomaterial Database

Physiologically-based pharmacokinetic pharmacodynamic parent-metabolite model of edoxaban to predict drug-drug-disease interactions: M4 contribution. 2023

Ruijuan Xu, and Wenyuan Liu, and Weihong Ge, and Hua He, and Qing Jiang

Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.

This study aimed to develop a physiologically-based pharmacokinetic pharmacodynamic (PBPK/PD) parent-metabolite model of edoxaban, an oral anticoagulant with a narrow therapeutic index, and to predict pharmacokinetic (PK)/PD profiles and potential drug-drug-disease interactions (DDDIs) in patients with renal impairment. A whole-body PBPK model with a linear additive PD model of edoxaban and its active metabolite M4 was developed and validated in SimCYP for healthy adults with or without interacting drugs. The model was extrapolated to situations including renal impairment and drug-drug interactions (DDIs). Observed PK and PD data in adults were compared with predicted data. The effect of several model parameters on the PK/PD response of edoxaban and M4 was investigated in sensitivity analysis. The PBPK/PD model successfully predicted PK profiles of edoxaban and M4 as well as anticoagulation PD responses with or without the influence of interacting drugs. For patients with renal impairment, the PBPK model successfully predicted the fold change in each impairment group. Inhibitory DDI and renal impairment had a synergistic effect on the increased exposure of edoxaban and M4, and their downstream anticoagulation PD effect. Sensitivity analysis and DDDI simulation show that renal clearance, intestinal P-glycoprotein activity, and hepatic OATP1B1 activity are the major factors affecting edoxaban-M4 PK profiles and PD responses. Anticoagulation effect induced by M4 cannot be ignored when OATP1B1 is inhibited or downregulated. Our study provides a reasonable approach to adjust the dose of edoxaban in several complicated scenarios especially when M4 cannot be ignored due to decreased OATP1B1 activity.

UI	MeSH Term	Description	Entries
D008954	Models, Biological	Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment.	Biological Model,Biological Models,Model, Biological,Models, Biologic,Biologic Model,Biologic Models,Model, Biologic
D011725	Pyridines	Compounds with a six membered aromatic ring containing NITROGEN. The saturated version is PIPERIDINES.
D003198	Computer Simulation	Computer-based representation of physical systems and phenomena such as chemical processes.	Computational Modeling,Computational Modelling,Computer Models,In silico Modeling,In silico Models,In silico Simulation,Models, Computer,Computerized Models,Computer Model,Computer Simulations,Computerized Model,In silico Model,Model, Computer,Model, Computerized,Model, In silico,Modeling, Computational,Modeling, In silico,Modelling, Computational,Simulation, Computer,Simulation, In silico,Simulations, Computer
D004347	Drug Interactions	The action of a drug that may affect the activity, metabolism, or toxicity of another drug.	Drug Interaction,Interaction, Drug,Interactions, Drug
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000328	Adult	A person having attained full growth or maturity. Adults are of 19 through 44 years of age. For a person between 19 and 24 years of age, YOUNG ADULT is available.	Adults
D000925	Anticoagulants	Agents that prevent BLOOD CLOTTING.	Anticoagulant Agent,Anticoagulant Drug,Anticoagulant,Anticoagulant Agents,Anticoagulant Drugs,Anticoagulation Agents,Indirect Thrombin Inhibitors,Agent, Anticoagulant,Agents, Anticoagulant,Agents, Anticoagulation,Drug, Anticoagulant,Drugs, Anticoagulant,Inhibitors, Indirect Thrombin,Thrombin Inhibitors, Indirect
D013844	Thiazoles	Heterocyclic compounds where the ring system is composed of three CARBON atoms, a SULFUR and NITROGEN atoms.	Thiazole
D051437	Renal Insufficiency	Conditions in which the KIDNEYS perform below the normal level in the ability to remove wastes, concentrate URINE, and maintain ELECTROLYTE BALANCE; BLOOD PRESSURE; and CALCIUM metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of PROTEINURIA) and reduction in GLOMERULAR FILTRATION RATE.	Kidney Insufficiency,Kidney Failure,Renal Failure,Failure, Kidney,Failure, Renal,Failures, Kidney,Failures, Renal,Insufficiency, Kidney,Kidney Failures,Kidney Insufficiencies,Renal Failures,Renal Insufficiencies