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Physiologically-based pharmacokinetics modeling to investigate formulation factors influencing the generic substitution of dabigatran etexilate.
- Source :
-
CPT: pharmacometrics & systems pharmacology [CPT Pharmacometrics Syst Pharmacol] 2021 Mar; Vol. 10 (3), pp. 199-210. Date of Electronic Publication: 2021 Feb 10. - Publication Year :
- 2021
-
Abstract
- The exposure-response relationship of direct acting oral anti-coagulants (DOACs) for bleeding risk is steep relative to ischemic stroke reduction. As a result, small changes in exposure may lead to bleeding events. The overall goal of this project was to determine the effect of critical formulation parameters on the pharmacokinetics (PKs) and thus safety and efficacy of generic DOACs. In this first installment of our overall finding, we developed and verified a physiologically-based PK (PBPK) model for dabigatran etexilate (DABE) and its metabolites. The model was developed following a middle out approach leveraging available in vitro and in vivo data. External validity of the model was confirmed by overlapping predicted and observed PK profiles for DABE as well as free and total dabigatran for a dataset not used during model development. The verified model was applied to interrogate the impact of modulating the microenvironment pH on DABE systemic exposure. The PBPK exploratory analyses highlighted the high sensitivity of DABE exposure to supersaturation ratio and precipitation kinetics.<br /> (© 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
- Subjects :
- Antithrombins adverse effects
Antithrombins chemistry
Biological Availability
Chemical Precipitation
Dabigatran adverse effects
Dabigatran chemistry
Drug Development
Drug Substitution statistics & numerical data
Factor Xa Inhibitors adverse effects
Factor Xa Inhibitors chemistry
Factor Xa Inhibitors pharmacokinetics
Hemorrhage chemically induced
Humans
Pharmacokinetics
Safety
Treatment Outcome
Antithrombins pharmacokinetics
Dabigatran pharmacokinetics
Drug Compounding methods
Drug Substitution methods
Ischemic Stroke prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 2163-8306
- Volume :
- 10
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- CPT: pharmacometrics & systems pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 33449439
- Full Text :
- https://doi.org/10.1002/psp4.12589