Physiologically‐based pharmacokinetics modeling to investigate formulation factors influencing the generic substitution of dabigatran etexilate
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 for...
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Online Access: | https://doi.org/10.1002/psp4.12589 |
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doaj-65b7b9c93afe4b8798d1ebe130028b672021-03-17T03:51:07ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062021-03-0110319921010.1002/psp4.12589Physiologically‐based pharmacokinetics modeling to investigate formulation factors influencing the generic substitution of dabigatran etexilateNashid Farhan0Rodrigo Cristofoletti1Sumit Basu2Sarah Kim3Karthik Lingineni4Sibo Jiang5Joshua D. Brown6Lanyan (Lucy) Fang7Lawrence J. Lesko8Stephan Schmidt9Department of Pharmaceutics Center for Pharmacometrics and Systems Pharmacology College of Pharmacy University of Florida Orlando Florida USADepartment of Pharmaceutics Center for Pharmacometrics and Systems Pharmacology College of Pharmacy University of Florida Orlando Florida USADepartment of Pharmaceutics Center for Pharmacometrics and Systems Pharmacology College of Pharmacy University of Florida Orlando Florida USADepartment of Pharmaceutics Center for Pharmacometrics and Systems Pharmacology College of Pharmacy University of Florida Orlando Florida USADepartment of Pharmaceutics Center for Pharmacometrics and Systems Pharmacology College of Pharmacy University of Florida Orlando Florida USADepartment of Pharmaceutics Center for Pharmacometrics and Systems Pharmacology College of Pharmacy University of Florida Orlando Florida USADepartment of Pharmaceutical Outcomes and Policy Center for Drug Evaluation and Safety College of Pharmacy University of Florida Gainesville Florida USAOffice of Research and Standards Office of Generic Drugs Center for Drug Evaluation and Research, US Food and Drug Administration Silver Spring Maryland USADepartment of Pharmaceutics Center for Pharmacometrics and Systems Pharmacology College of Pharmacy University of Florida Orlando Florida USADepartment of Pharmaceutics Center for Pharmacometrics and Systems Pharmacology College of Pharmacy University of Florida Orlando Florida USAAbstract 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.https://doi.org/10.1002/psp4.12589 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Nashid Farhan Rodrigo Cristofoletti Sumit Basu Sarah Kim Karthik Lingineni Sibo Jiang Joshua D. Brown Lanyan (Lucy) Fang Lawrence J. Lesko Stephan Schmidt |
spellingShingle |
Nashid Farhan Rodrigo Cristofoletti Sumit Basu Sarah Kim Karthik Lingineni Sibo Jiang Joshua D. Brown Lanyan (Lucy) Fang Lawrence J. Lesko Stephan Schmidt Physiologically‐based pharmacokinetics modeling to investigate formulation factors influencing the generic substitution of dabigatran etexilate CPT: Pharmacometrics & Systems Pharmacology |
author_facet |
Nashid Farhan Rodrigo Cristofoletti Sumit Basu Sarah Kim Karthik Lingineni Sibo Jiang Joshua D. Brown Lanyan (Lucy) Fang Lawrence J. Lesko Stephan Schmidt |
author_sort |
Nashid Farhan |
title |
Physiologically‐based pharmacokinetics modeling to investigate formulation factors influencing the generic substitution of dabigatran etexilate |
title_short |
Physiologically‐based pharmacokinetics modeling to investigate formulation factors influencing the generic substitution of dabigatran etexilate |
title_full |
Physiologically‐based pharmacokinetics modeling to investigate formulation factors influencing the generic substitution of dabigatran etexilate |
title_fullStr |
Physiologically‐based pharmacokinetics modeling to investigate formulation factors influencing the generic substitution of dabigatran etexilate |
title_full_unstemmed |
Physiologically‐based pharmacokinetics modeling to investigate formulation factors influencing the generic substitution of dabigatran etexilate |
title_sort |
physiologically‐based pharmacokinetics modeling to investigate formulation factors influencing the generic substitution of dabigatran etexilate |
publisher |
Wiley |
series |
CPT: Pharmacometrics & Systems Pharmacology |
issn |
2163-8306 |
publishDate |
2021-03-01 |
description |
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. |
url |
https://doi.org/10.1002/psp4.12589 |
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