PMID- 37101392
OWN - NLM
STAT- MEDLINE
DCOM- 20230817
LR  - 20230818
IS  - 2163-8306 (Electronic)
IS  - 2163-8306 (Linking)
VI  - 12
IP  - 8
DP  - 2023 Aug
TI  - Physiologically-based pharmacokinetic pharmacodynamic parent-metabolite model of 
      edoxaban to predict drug-drug-disease interactions: M4 contribution.
PG  - 1093-1106
LID - 10.1002/psp4.12977 [doi]
AB  - 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.
CI  - (c) 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by 
      Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and 
      Therapeutics.
FAU - Xu, Ruijuan
AU  - Xu R
AD  - Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of 
      Medical School, Nanjing University, Nanjing, China.
AD  - Division of Sports Medicine and Adult Reconstructive Surgery, Department of 
      Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical 
      School, Nanjing University, Nanjing, China.
FAU - Liu, Wenyuan
AU  - Liu W
AD  - Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of 
      Medical School, Nanjing University, Nanjing, China.
AD  - Department of Pharmacy, Nanjing Drum Tower Hospital Clinical College of Nanjing 
      University of Chinese Medicine, Nanjing, China.
FAU - Ge, Weihong
AU  - Ge W
AD  - Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of 
      Medical School, Nanjing University, Nanjing, China.
AD  - Department of Pharmacy, Nanjing Drum Tower Hospital Clinical College of Nanjing 
      University of Chinese Medicine, Nanjing, China.
FAU - He, Hua
AU  - He H
AD  - Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 
      Nanjing, China.
FAU - Jiang, Qing
AU  - Jiang Q
AD  - Division of Sports Medicine and Adult Reconstructive Surgery, Department of 
      Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical 
      School, Nanjing University, Nanjing, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230519
PL  - United States
TA  - CPT Pharmacometrics Syst Pharmacol
JT  - CPT: pharmacometrics & systems pharmacology
JID - 101580011
RN  - NDU3J18APO (edoxaban)
RN  - 0 (Thiazoles)
RN  - 0 (Pyridines)
RN  - 0 (Anticoagulants)
SB  - IM
MH  - Adult
MH  - Humans
MH  - *Thiazoles/pharmacology
MH  - Pyridines/pharmacokinetics
MH  - *Renal Insufficiency/metabolism
MH  - Drug Interactions
MH  - Anticoagulants
MH  - Models, Biological
MH  - Computer Simulation
PMC - PMC10431043
COIS- The authors declared no competing interests for this work.
EDAT- 2023/04/27 06:42
MHDA- 2023/08/17 06:42
PMCR- 2023/05/19
CRDT- 2023/04/27 01:33
PHST- 2023/04/13 00:00 [revised]
PHST- 2022/12/22 00:00 [received]
PHST- 2023/04/18 00:00 [accepted]
PHST- 2023/08/17 06:42 [medline]
PHST- 2023/04/27 06:42 [pubmed]
PHST- 2023/04/27 01:33 [entrez]
PHST- 2023/05/19 00:00 [pmc-release]
AID - PSP412977 [pii]
AID - 10.1002/psp4.12977 [doi]
PST - ppublish
SO  - CPT Pharmacometrics Syst Pharmacol. 2023 Aug;12(8):1093-1106. doi: 
      10.1002/psp4.12977. Epub 2023 May 19.