Physiologically-based pharmacokinetic modeling and simulation of drug-drug interactions between azole antifungals, macrolide antibiotics or proton pump inhibitors and tacrolimus for provision of quantitative information to clinical practice

[Speaker] Yukio Otsuka:1
[Co-author] Akira Koibuchi:1, Atsunori Kaibara:1, Yukako Tsukamoto:2, Kumi Koide:2, Kazuya Iwamoto:2, Masato Yamazaki:2, Manabu Murakami:1, Naoko Sato:2
1:Clinical Pharmacology, Development, Astellas Pharma Inc., Japan, 2:Medical Communications, Medical Affairs, Astellas Pharma Inc., Japan

[Background] Tacrolimus is mainly metabolized by CYP3A4 and CYP3A5 and used with care when co-administered with the drugs which have inhibitory effects to these enzymes. There are a lot of articles or case reports for tacrolimus regarding drug-drug interaction (DDI) available in public. Unfortunately, it is quite difficult to directly compare the DDI effects of concomitant drugs against tacrolimus due to large discrepancies in reported values of exposure change by DDI even for the same combinations and doses, and thus the knowledge about the DDI effects has not been well accumulated nor fully utilized. The present study aims to rank relative DDI potencies of commonly used concomitant drugs such as azole antifungals, macrolide antibiotics or proton pump inhibitors (PPIs) on tacrolimus exposure using physiologically-based pharmacokinetic (PBPK) model as useful bedside information.
[Method] The PBPK models for tacrolimus, voriconazole, azithromycin, vonoprazan, lansoprazole, rabeprazole and esomeprazole were developed using Simcyp simulator (v16.1). The software containing PBPK models of itraconazole, fluconazole, erythromycin, clarithromycin and omeprazole were used with slight modification, if needed. DDI simulations between tacrolimus and azole antifungals, macrolide antibiotics, or PPIs were performed with software generated virtual healthy volunteer population.
[Results] The simulated DDI effects are strong in the order of voriconazole= itraconazole> fluconazole, clarithromycin> erythromycin> azithromycin and vonoprazan> lansoprazole= omeprazole> esomeprazole= rabeprazole, in azole antifungals, macrolide antibiotics and PPIs, respectively. No DDI were simulated in esomeprazole and rabeprazole. Interestingly, vonoprazan, which has not been considered to inhibit CYP3A in clinical settings, was simulated moderate inhibitory effects on tacrolimus blood exposure. Care should be taken when vonoprazan is co-administered with tacrolimus.
[Conclusion] In the present study, DDI effects of azole antifungals, macrolide antibiotics and PPIs on tacrolimus exposure are simulated with PBPK model and compared directly within the same drug classes. We believe the information provided from current study contributes to safe and efficacious therapy of tacrolimus in clinical settings.
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