PI-078 - PHARMACOKINETIC INTERACTION STUDIES OF COADMINISTRATION OF TAZEMETOSTAT WITH FLUCONAZOLE, REPAGLINIDE, OR OMEPRAZOLE IN PATIENTS WITH ADVANCED MALIGNANCIES.

Y. Chen¹, R. Teng², J. Ogier³; ¹Ipsen, Cambridge, Massachusetts, USA, ²CareCeutics, LLC, Berwyn, Pennsylvania, USA, ³Ipsen Innovation, Les Ulis, France.

Background: Tazemetostat, an enhancer of zeste homolog 2 (EZH2) inhibitor, is approved for patients with follicular lymphoma and epithelioid sarcoma. In vitro tests have indicated that tazemetostat is a substrate of CYP3A and inhibits CYP2C8 and CYP2C19. Its solubility is pH dependent and gastric pH may alter its oral absorption. This study assessed the interaction potential of tazemetostat with fluconazole (moderate CYP3A inhibitor), repaglinide (sensitive CYP2C8 substrate), and omeprazole (sensitive CYP2C19 substrate and proton pump inhibitor).

Methods: This was an open-label, two-part, fixed-sequence study in patients with advanced malignancies. In Part A, 16 patients received tazemetostat 400 mg twice daily (BID) for 24 days (D) and fluconazole 400 mg once daily on D16–19. Plasma tazemetostat concentrations for pharmacokinetic (PK) analysis was assessed on D15 and D19. In Part B, 16 patients received a single cocktail dose of repaglinide 0.25 mg and omeprazole 20 mg on D1 and D16, and tazemetostat 800 mg BID on D2–19. Patients continued omeprazole on D17–19. Plasma concentrations of tazemetostat, repaglinide, and omeprazole on D1, D16, and D19 were quantified for PK analyses. Patients were permitted to continue tazemetostat 800 mg BID from D25 and D20, in Parts A and B, respectively.

Results: Coadministration of tazemetostat with fluconazole increased tazemetostat Cmax by 2.27-fold (90% confidence interval 1.75–2.95) and AUC0–8 by 3.07-fold (2.56–3.66). Coadministration of tazemetostat with repaglinide increased repaglinide Cmax by 51% (0.82–2.78) and AUC0–8 by 80% (1.12–2.87). Coadministration of tazemetostat with omeprazole increased tazemetostat Cmax by 25% (0.76–1.35) and AUC0–8 by 26% (0.87–1.82). Omeprazole Cmax (0.82-fold [0.50–1.35]) and AUC0–8 (0.80-fold [0.52–1.22]) were unaffected by tazemetostat.

Conclusion: Tazemetostat exposure was moderately increased by fluconazole, and concomitant dosing of moderate CYP3A inhibitors with tazemetostat should be discouraged. Coadministration of tazemetostat with repaglinide (sensitive CYP2C8 substrate) mildly increased repaglinide exposure, whereas tazemetostat had no impact on omeprazole exposure (sensitive CYP2C19 substrate). The effect of gastric pH increase by omeprazole (proton pump inhibitor) on tazemetostat exposure was modest and unlikely clinically relevant.