PII-061 - CLINICAL DRUG-DRUG INTERACTION STUDIES THROUGH CYTOCHROME P450 3A (CYP3A) AND P-GLYCOPROTEIN (P-GP) FOR BAY 2927088 USING ITRACONAZOLE (ITZ), CARBAMAZEPINE (CBZ) AND MIDAZOLAM (MDZ)

B. Brennan¹, M. Damaske², F. Hafner³, I. Piel³, C. von Buehler³, M. Niehues², N. Jungmann³, S. Reif², S. Prendergast⁴, P. Lienau², B. Ploeger², C. Chen⁵; ¹Bayer, Whippany, NJ, USA, ²Bayer, Berlin, Germany, ³Bayer, Wuppertal, Germany, ⁴Bayer, Reading, United Kingdom, ⁵Bayer, Whippany, USA.

Background: BAY 2927088 is an oral reversible tyrosine kinase inhibitor (TKI) being developed for treatment of adult patients with unresectable or metastatic non-small cell lung cancer harboring HER2 activating mutations. In vitro, BAY 2927088 is primarily metabolized by CYP3A4 and is a substrate of P-gp. BAY 2927088 also shows evidence for CYP3A inhibition and induction. Clinical drug-drug interaction studies were performed using strong inhibitors / inducers of CYP3A4 and P-gp as well as a sensitive CYP3A4 substrate.

Methods: Two studies were performed, the first was an open label, 2-arm, fixed sequence, crossover study to investigate the effects of ITZ and CBZ on the pharmacokinetics of BAY 2927088 in 15 healthy participants per arm. The second was an open label, fixed sequence, crossover study to investigate the effect of BAY 2927088 on the pharmacokinetics of MDZ in 15 healthy participants. Safety and tolerability were closely monitored throughout the studies.

Results: Administration of BAY 2927088 with ITZ 200 mg QD increased BAY 2927088 AUC approximately 2.25-fold and Cmax 1.60-fold. Administration of BAY 2927088 with CBZ, titrated to a dose of 300 mg BID, reduced BAY 2927088 AUC by approximately 80% and Cmax by approximately 58%. Administration of BAY 2927088 20 mg BID for 10 days followed by a single oral dose of MDZ 1 mg increased MDZ AUC by 1.95-fold and Cmax by 1.79-fold compared to a single dose of MDZ 1 mg alone. BAY 2927088 was safe and tolerable in healthy volunteers in both studies.

Conclusion: BAY 2927088 exposure was increased by the strong CYP3A4 and P-gp inhibitor itraconazole and reduced by the strong CYP3A4 and P-gp inducer, carbamazepine. BAY 2927088 increased exposure of MDZ, indicating that BAY 2927088 is a weak CYP3A4 inhibitor.