Schiller, Hilmar, Huth, Felix, Schuhler, Carole, Drollmann, Anton Franz, Kaul, Martin, Woessner, Ralph, Shah, Bharti, Weis, Wendy and End, Peter (2022) Novel Bruton’s tyrosine kinase inhibitor remibrutinib: Assessment of drug-drug interaction potential as a perpetrator of cytochrome P450 enzymes and drug transporters and the impact of covalent binding on possible drug interactions. European journal of pharmaceutical sciences, 172. ISSN 09280987

Abstract

Purpose
Pharmacokinetic drug–drug interactions (DDIs) are investigated to ensure safety for patients receiving concomitant medications. Here, we present results of in vitro studies and a clinical study to assess the DDI potential of Bruton’s Tyrosine kinase inhibitor, remibrutinib as an inhibitor of drug-metabolising enzymes and drug transporters, and as an inducer. The pharmacokinetics of oral hormonal contraceptives (OC) in combination with remibrutinib were also evaluated. Remibrutinib is a covalent inhibitor of BTK and carries a reactive acrylamide moiety (warhead), so the potential contribution of covalent binding to observed interactions was investigated.

Methods
DDI assessment was based on initial in vitro studies, a clinical DDI study and an endogenous biomarker assessment. Beyond the potential effect on OC, the prediction of concomitant medications with remibrutinib and Cytochrome P450 (CYP) metabolism was evaluated. The impact of covalent binding was assessed by synthesising an identical reference molecule but with an inactivated warhead.

Results
Overall, the study revealed minor DDIs with limited clinical relevance for remibrutinib with CYP enzymes and drug transporters. Interestingly, the reactive warhead of remibrutinib had no impact on CYP enzyme and transporter inhibition, including time-dependent inhibition of CYP3A4, but may increase the induction potential of remibrutinib.
Observed inhibition of metabolic enzymes indicated that remibrutinib is a weak inhibitor of CYP3A4 and CYP2C9 and is not a clinically relevant inhibitor of uptake and efflux transporters, with the exception of intestinal P-glycoprotein and breast cancer resistance protein inhibition. .

Conclusion
Oral contraceptives may be safely administered and are effective when given with pharmacologically relevant doses of remibrutinib.

Item Type:	Article
Date Deposited:	24 May 2022 00:45
Last Modified:	24 May 2022 00:45
URI:	https://oak.novartis.com/id/eprint/45877