In vitro–in vivo correlation of the drug–drug interaction potential of antiretroviral HIV treatment regimens on CYP1A1 substrate riociguat

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. ARTICLE HISTORY

Basic aspects of pathophysiology, diagnosis and treatment of patients with pulmonary arterial hypertension associated with human immunodeficiency virus infection: what has been achieved and what remains to be achieved?

“…и др. проводили опыты в системе in vitro [18], определяя ингибирующий потенциал компонентов шести антиретровирусных комбинаций на метаболизм риоцигуата методом оценки в рекомбинантных человеческих CYP1A1 и CYP3A4, а также в гепатоцитах человека, проявляющих активность как CYP1A1, так и CYP3A4.…”

The achievements of the modern specific therapy of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: focus on the stimulator of soluble guanylate cyclase riociguat

“…Влияние препаратов, содержащих только сильные ингибиторы CYP3A4, например ритонавир, было менее выраженным. Следует помнить, что, как и при ЛАГ-ВПС, при ЛАГ-ВИЧ риоцигуат не зарегистрирован в Российской Федерации, а полученные в настоящей работе данные служат хорошим основанием для дальнейших клинических исследований [12,18].…”

Evaluating Riociguat in the Treatment of Pulmonary Arterial Hypertension: A Real-World Perspective

“…overt side effects and need close observation. [15][16][17] In the modern era, it is important to be mindful that ritonavir (along with nirmatrelvir) is active component in Paxlovid TM , the only oral antiviral approved for outpatient use in the treatment of COVID19. Because ritonavir is a potent inhibitor of cytochrome P450, Paxlovid is contraindicated in patients taking riociguat.…”