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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 12/2017

01-12-2017 | Original Research Article

Target-Mediated Drug Disposition Pharmacokinetic–Pharmacodynamic Model of Bosentan and Endothelin-1

Authors: Anke-Katrin Volz, Andreas Krause, Walter Emil Haefeli, Jasper Dingemanse, Thorsten Lehr

Published in: Clinical Pharmacokinetics | Issue 12/2017

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Abstract

Background and Objectives

Bosentan is a competitive antagonist on endothelin receptor A and B (ETA and ETB), displacing the endogenous binding partner endothelin-1 (ET-1) from its binding sites. After administration of escalating single doses of 10–750 mg as an intravenous (i.v.) infusion, bosentan showed dose-dependent pharmacokinetics (PK). The aim of this analysis was to develop a PK model of bosentan after i.v. administration including competitive antagonism with ET-1 and to analyze its influence on blood pressure and heart rate with a combined pharmacokinetic/pharmacodynamic (PK/PD) model.

Methods

PK/PD data from 70 young male Caucasian subjects were analyzed after single i.v. administration of 10, 50, 250, 500, and 750 mg of bosentan. Population analyses, simulations, and evaluation were performed using a non-linear mixed-effects modeling approach.

Results

The PK of bosentan was best described by a two-compartment, target-mediated drug disposition (TMDD) model. ET-1 plasma and urine profiles were successfully integrated into the bosentan two-compartment, TMDD model encompassing competition for the same receptor. A multiple-peak phenomenon of bosentan plasma concentrations after i.v. administration was best described by a diurnal expression or reappearance of ET receptors on the cell surface. Blood pressure was best described by an E max model; heart rate was modeled as a compensatory effect of changes in blood pressure.

Conclusion

The developed competitive PK/PD model of bosentan and ET-1 after i.v. administration provides a first step towards understanding the complex PK properties of bosentan and offers a valuable tool for future PK/PD research.
Appendix
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Metadata
Title
Target-Mediated Drug Disposition Pharmacokinetic–Pharmacodynamic Model of Bosentan and Endothelin-1
Authors
Anke-Katrin Volz
Andreas Krause
Walter Emil Haefeli
Jasper Dingemanse
Thorsten Lehr
Publication date
01-12-2017
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 12/2017
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-017-0534-4

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