Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo.

Dimitrios Vagiannis,Anselm Morell,Youssif Budagaga,Sarah Kammerer,Eva Novotná,Jan-Heiner Küpper,Adam Skarka,Jakub Hofman,Yu Zhang,Ivo Hanke,Tomáš Rozkoš

doi:10.3390/ijms222111936

Abstract

Tepotinib is a novel tyrosine kinase inhibitor recently approved for the treatment of non-small cell lung cancer (NSCLC). In this study, we evaluated the tepotinib’s potential to perpetrate pharmacokinetic drug interactions and modulate multidrug resistance (MDR). Accumulation studies showed that tepotinib potently inhibits ABCB1 and ABCG2 efflux transporters, which was confirmed by molecular docking. In addition, tepotinib inhibited several recombinant cytochrome P450 (CYP) isoforms with varying potency. In subsequent drug combination experiments, tepotinib synergistically reversed daunorubicin and mitoxantrone resistance in cells with ABCB1 and ABCG2 overexpression, respectively. Remarkably, MDR-modulatory properties were confirmed in ex vivo explants derived from NSCLC patients. Furthermore, we demonstrated that anticancer effect of tepotinib is not influenced by the presence of ABC transporters associated with MDR, although monolayer transport assays designated it as ABCB1 substrate. Finally, tested drug was observed to have negligible effect on the expression of clinically relevant drug efflux transporters and CYP enzymes. In conclusion, our findings provide complex overview on the tepotinib’s drug interaction profile and suggest a promising novel therapeutic strategy for future clinical investigations.

Highlights

Licensee MDPI, Basel, Switzerland.For decades, lung cancer has represented the deadliest type of malignancy within oncological diseases
In the case of ABCB1, tepotinib showed the highest affinity for the M- and Hoechst binding site (H-site) (Figure 1A bottom left)
Considering tepotinib’s steady state Cmax observed at recommended dosing of 500 mg daily (2.62 μM) [11], unbound fraction [12] and Food and Drug Administration (FDA)/European Medicines Agency (EMA) guidelines [10,13], only ABCB1 and CYP2C9 inhibitions can be considered potentially clinically relevant for perpetrating systemic pharmacokinetic drug interactions (DIs). This statement is in accordance with the results of DI study in healthy subjects, where tepotinib significantly increased AUC and Cmax of DI-sensitive ABCB1 substrate dabigatran etexilate, but it failed to exert the effect on CYP3A4 substrate midazolam [14]

Summary

Introduction

Licensee MDPI, Basel, Switzerland.For decades, lung cancer has represented the deadliest type of malignancy within oncological diseases. The clinical outcomes of its treatment are hampered by the development of drug resistance, which can be based on pharmacodynamic and pharmacokinetic principles [1]. P450 (CYP) biotransformation enzymes play crucial pharmacokinetic roles through orchestrating absorption, distribution and elimination of numerous drugs. Due to this published maps and institutional affil-. ABCB1, ABCG2, ABCC1 and CYP3A4 were recognized as important pharmacokinetic mechanisms of oncological multidrug resistance (MDR). These proteins are overexpressed in several tumor types, where they decrease the efficacy of anticancer drugs by efflux or metabolism, respectively [4,5]

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