PII-022 - CLINICAL DRUG-DRUG INTERACTION STUDIES INVESTIGATING THE EFFECT OF BAY 2927088 ON P-GP AND BCRP USING DABIGATRAN ETEXILATE AND ROSUVASTATIN

C. Chen¹, M. Damaske², F. Hafner³, R. Frick³, S. Reif², S. Prendergast⁴, P. Lienau², B. Ploeger², B. Brennan⁵; ¹Bayer, Whippany, USA, ²Bayer, Berlin, Germany, ³Bayer, Wuppertal, Germany, ⁴Bayer, Reading, United Kingdom, ⁵Bayer, Whippany, NJ, USA.

Background: BAY 2927088 is an oral reversible tyrosine kinase inhibitor being developed for treatment of adult patients with unresectable or metastatic non-small cell lung cancer harboring HER2 activating mutations. BAY 2927088 shows in vitro evidence of inhibition of P-gp and BCRP. A clinical drug-drug interaction study was performed using sensitive substrates of these transporters. In addition, coproporphyrins as endogenous biomarkers for OATP 1B1/1B3 inhibition were explored.

Methods: This was an open label, fixed sequence, crossover study to investigate the effect of BAY 2927088 on the pharmacokinetics of dabigatran etexilate or rosuvastatin in 15 healthy volunteers. Single doses of dabigatran etexilate 75 mg, or rosuvastatin 10 mg, were administered alone or in combination with BAY 2927088 20 mg BID dosing to steady-state. Dabigatran and rosuvastatin PK and coproporphyrin I and III samples were collected. Safety and tolerability were closely monitored throughout the study.

Results: Administration of BAY 2927088 20 mg BID increased unconjugated dabigatran AUC by 39% and decreased Cmax by less than 5%. Administration of BAY 2927088 20 mg BID increased rosuvastatin AUC by 25% and Cmax by 37%. No change was observed in coproporphyrins supporting that BAY 2927088 is not an inhibitor of OATP 1B1 or 1B3. BAY 2927088 was safe and well tolerated in healthy volunteers.

Conclusion: BAY 2927088 slightly increased exposure of unconjugated dabigatran by 39% and rosuvastatin by 25% indicating a weak inhibition of P-gp and BCRP, respectively.