Ruben de Kanter1, Patricia N Sidharta2, Stéphane Delahaye3, Carmela Gnerre3, Jerome Segrestaa3, Stephan Buchmann4, Christopher Kohl3, Alexander Treiber3. 1. Preclinical Pharmacokinetics and Metabolism, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland. ruben.de-kanter@actelion.com. 2. Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland. 3. Preclinical Pharmacokinetics and Metabolism, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland. 4. Preformulation and Preclinical Galenics, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
Abstract
INTRODUCTION: Macitentan is a novel dual endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). It is metabolized by cytochrome P450 (CYP) enzymes, mainly CYP3A4, to its active metabolite ACT-132577. METHODS: A physiological-based pharmacokinetic (PBPK) model was developed by combining observations from clinical studies and physicochemical parameters as well as absorption, distribution, metabolism and excretion parameters determined in vitro. RESULTS: The model predicted the observed pharmacokinetics of macitentan and its active metabolite ACT-132577 after single and multiple dosing. It performed well in recovering the observed effect of the CYP3A4 inhibitors ketoconazole and cyclosporine, and the CYP3A4 inducer rifampicin, as well as in predicting interactions with S-warfarin and sildenafil. The model was robust enough to allow prospective predictions of macitentan-drug combinations not studied, including an alternative dosing regimen of ketoconazole and nine other CYP3A4-interacting drugs. Among these were the HIV drugs ritonavir and saquinavir, which were included because HIV infection is a known risk factor for the development of PAH. CONCLUSION: This example of the application of PBPK modeling to predict drug-drug interactions was used to support the labeling of macitentan (Opsumit).
INTRODUCTION:Macitentan is a novel dual endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). It is metabolized by cytochrome P450 (CYP) enzymes, mainly CYP3A4, to its active metabolite ACT-132577. METHODS: A physiological-based pharmacokinetic (PBPK) model was developed by combining observations from clinical studies and physicochemical parameters as well as absorption, distribution, metabolism and excretion parameters determined in vitro. RESULTS: The model predicted the observed pharmacokinetics of macitentan and its active metabolite ACT-132577 after single and multiple dosing. It performed well in recovering the observed effect of the CYP3A4 inhibitors ketoconazole and cyclosporine, and the CYP3A4 inducer rifampicin, as well as in predicting interactions with S-warfarin and sildenafil. The model was robust enough to allow prospective predictions of macitentan-drug combinations not studied, including an alternative dosing regimen of ketoconazole and nine other CYP3A4-interacting drugs. Among these were the HIV drugs ritonavir and saquinavir, which were included because HIV infection is a known risk factor for the development of PAH. CONCLUSION: This example of the application of PBPK modeling to predict drug-drug interactions was used to support the labeling of macitentan (Opsumit).
Authors: Ping Zhao; Isabelle Ragueneau-Majlessi; Lei Zhang; John M Strong; Kellie S Reynolds; Rene H Levy; Kenneth E Thummel; Shiew-Mei Huang Journal: J Clin Pharmacol Date: 2009-03 Impact factor: 3.126