The utility of CYP3A activity endogenous markers for evaluating drug-drug interaction between sildenafil and CYP3A inhibitors in healthy subjects.

Soyoung Lee, Andrew HyoungJin Kim, Sumin Yoon, Jieon Lee, Yujin Lee, Sang Chun Ji, Seo Hyun Yoon, SeungHwan Lee, Kyung-Sang Yu, In-Jin Jang, Joo-Youn Cho

Drug metabolism and pharmacokinetics 2021 Feb

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Cytochrome P450 (CYP) 3A-related drug-drug interaction (DDI) studies are needed during drug development to determine clinical interaction effects. We aimed to evaluate DDI between sildenafil and two CYP3A inhibitors, clarithromycin and itraconazole, regarding the changes in pharmacokinetics and endogenous markers. An open-label, one-sequence, one-period, two-treatment parallel study was conducted in 32 healthy Korean subjects. Each of 16 subjects were randomly assigned to the clarithromycin and itraconazole groups. Both groups received a single dose of sildenafil 25 mg as a control, and either clarithromycin 250 mg or itraconazole 100 mg was administered four times to inhibit CYP3A activity. Pharmacokinetics of sildenafil showed the similar magnitude of inhibitory effects of the two inhibitors on total CYP3A activity; both inhibitors similarly increased systemic exposure of sildenafil by 2-fold. Urinary 6β-OH-cortisone/cortisone and plasma 4β-OH-cholesterol were significantly decreased after clarithromycin administration but not after itraconazole. A significant correlation between sildenafil CL/F and metabolic markers of CYP3A activity was observed after clarithromycin administration. We confirmed that sildenafil has moderate pharmacokinetic interaction with clarithromycin and itraconazole. Endogenous markers well reflected the CYP3A inhibition of clarithromycin, suggesting possible utility in DDI study with moderate to strong CYP3A inhibition; however, there are limitations in predicting intestinal CYP3A mediated DDI. Copyright © 2020 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Citation

Soyoung Lee, Andrew HyoungJin Kim, Sumin Yoon, Jieon Lee, Yujin Lee, Sang Chun Ji, Seo Hyun Yoon, SeungHwan Lee, Kyung-Sang Yu, In-Jin Jang, Joo-Youn Cho. The utility of CYP3A activity endogenous markers for evaluating drug-drug interaction between sildenafil and CYP3A inhibitors in healthy subjects. Drug metabolism and pharmacokinetics. 2021 Feb;36:100368