AI Article Synopsis
- Macitentan is a new drug designed to treat pulmonary arterial hypertension (PAH) by blocking endothelin receptors and is primarily metabolized by the CYP3A4 enzyme to its active form, ACT-132577.
- A pharmacokinetic model was developed using clinical data and laboratory measurements to understand how the drug behaves in the body, including how it gets absorbed, distributed, metabolized, and excreted.
- The model successfully predicted the drug's interactions with other medications and was instrumental in providing information for the labeling of macitentan, highlighting its potential interactions with drugs like ketoconazole and HIV treatments.
Article 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).
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| http://dx.doi.org/10.1007/s40262-015-0322-y | DOI Listing |
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