030: Drug-Drug Interaction of Celecoxib With Navitoclax in Subjects With Myeloproliferative Neoplasms (MPN)

Statement of Purpose: Navitoclax is an orally bioavailable B-cell lymphoma-2 (Bcl-2) family protein inhibitor that binds and inhibits antiapoptotic Bcl-2 family proteins with high affinity to Bcl-XL, Bcl-2, and Bcl-W which is currently being evaluated for the treatment of myelofibrosis (MF) in combination with ruxolitinib. In vitro results suggest that navitoclax has a potential for Cytochrome P450 2C9 enzyme (CYP2C9) inhibition. Therefore, the purpose of this study was to evaluate impact of navitoclax multiple dosing on celecoxib (a sensitive CYP2C9 substrate) pharmacokinetics (PK).

Description of Methods & Materials: This was a Phase 1, open label, multicenter, multicohort study in adult male and female subjects with MPN. The effect of multiple doses (300 mg) of daily navitoclax (Days 3 and beyond) on PK of single-dose celecoxib (100 mg) administered on Day 1 and Day 7 was investigated in Part 4 of the study (N=15). Blood samples for celecoxib were collected on Day 1 when dosed alone and after co-administration with navitoclax on Day 7 up to 96 hr. Individual PK parameters of celecoxib (e.g., T_max, C_max, AUC_inf, and t_1/2) were calculated using non-compartmental analysis in Phoenix WinNonlin v8.2. Central value ratios (90% confidence intervals) for C_max and AUC_inf (Day 7 vs Day 1) were calculated to assess the DDI. Safety was evaluated throughout the study.

Data & Results: Co-administration of navitoclax with celecoxib resulted in a non-significant decrease in celecoxib C_max by 9%, and AUC_inf increase by 21%. The median T_max of celecoxib increased slightly (3 hrs vs 2 hrs) with navitoclax co-administration. Celecoxib mean apparent elimination half-life increased from 5.3 hr to 7.3 hr when co-administered with navitoclax. No new or unexpected safety findings were observed.

Interpretation, Conclusion or Significance: Navitoclax did not increase celecoxib systemic exposures to a clinically significant level; hence, no dose adjustment is required for celecoxib (or any CYP2C9 substrate) when co-administered with navitoclax.

Disclosures: This study was funded by AbbVie. AbbVie contributed to the research, and interpretation of data, writing, reviewing, and approving the publication. All authors are AbbVie employees and may hold AbbVie stocks or options. P.G., D.S., M.M. and N.D have no COI disclosures.