In vitro–in vivo correlation of the drug–drug interaction potential of antiretroviral HIV treatment regimens on CYP1A1 substrate riociguat. (2nd November 2019)

• Record Type: Journal Article
• Authors: Jungmann, Natalia A.; Lang, Dieter; Saleh, Soundos; Van Der Mey, Dorina; Gerisch, Michael
• Is Part Of: Expert opinion on drug metabolism and toxicology. Volume 15:Number 11(2019)
• Page Start: 975
• Page End: 984
• Publication Date: 2019-11-02
• Subjects: Antivirals -- cytochrome p450 -- in vitro-in vivo prediction (IVIVE) -- liver/hepatic -- drug-drug interactions -- enzyme inhibitors -- pharmacokinetics; Drugs -- Toxicology -- Periodicals; Drugs -- Metabolism -- Periodicals; 615.7
• DOI: 10.1080/17425255.2019.1681968
• Languages: English
• ISSNs: 1742-5255

Abstract

ABSTRACT: Objectives : Riociguat is a soluble guanylate cyclase stimulator licensed for the treatment of pulmonary arterial hypertension (PAH), a potentially fatal complication of human immunodeficiency virus infection. This study investigated the inhibitory potency of selected antiretroviral regimens on the metabolic clearance of riociguat. Methods : The inhibitory potential of the components of six antiretroviral combinations (ATRIPLA® (efavirenz/emtricitabine/tenofovir disoproxil), COMPLERA® (rilpivirine/emtricitabine/tenofovir disoproxil), STRIBILD® (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil), TRIUMEQ® (abacavir/dolutegravir/lamivudine), and two ritonavir-boosted regimens) on riociguat metabolism were evaluated in recombinant human CYP1A1 and CYP3A4 as well as in human hepatocytes exhibiting both CYP1A1 and CYP3A4 activity. In vitro-in vivo correlation was performed between calculated and observed increases in riociguat exposure in vivo . Results : Using both in vitro systems, the predicted increase in exposure of riociguat was highest with components of TRIUMEQ® followed by COMPLERA®, ATRIPLA®, STRIBILD®, and the ritonavir-boosted regimens. Further experiments in human hepatocytes confirmed CYP1A1 to be the predominant enzyme in the metabolic clearance of riociguat. Conclusion : Antiretroviral treatment containing the potent CYP1A1 inhibitor abacavir had the greatest impact on riociguat metabolic clearance. The impact of comedications containing only strong CYP3A4 inhibitors e.g. ritonavir was less pronounced, suggesting a benefit of riociguat over PAH-targeting medications with contraindications for use with strong CYP3A4 inhibitors.