LB-013 - PHYSIOLOGICALLY BASED ABSORPTION AND PHARMACOKINETIC MODEL FOR RIVOCERANIB AND ITS MAIN METABOLITE TO ASSESS POTENTIAL CYP3A4-MEDIATED DDI RISK.

J. Novakovic¹, G. Fraczkiewicz¹, J. Heckman², B. Strickland², S. Jang², M. Zhou³, N. Djebli⁴; ¹Simulations Plus Inc, Lancaster, CA, United States, ²Elevar Therapeutics, Salt Lake City, UT, United States, ³Luszana Biotechnology, West Winsor Township, NJ, United States, ⁴Luszana Biotechnology, Basel, Switzerland.

Background: PBPK model for anticancer drug rivoceranib (RIV) was developed and validated to assess potential risk of CYP3A4-mediated DDIs.

Methods: In vivo distribution of RIV was modeled using GastroPlus default Kp estimation method [1]. Systemic clearance was parameterized via CYP3A4 and 2D6 saturable kinetics (Km, Vmax) [2]. PK data of RIV and metabolite M1-1 upon RIV oral doses of 81-750 mg, were used in model development. Clinical DDI studies with rifampicin or itraconazole were used to assess model performance. Validated model was applied to project RIV CYP3A4-mediated DDI with ranitidine (weak inhibitor), fluconazole (moderate inhibitor), and efavirenz (moderate inducer).

Results: PBPK model adequately described RIV and M1-1 exposures (Fig 1A), elimination via CYP3A4 and 2D6 (Fig 1B), magnitude of DDIs (Fig 1C and 1D), and food effect (not shown). Predicted/observed AUC0-t and Cmax across fasted, fed, and DDI studies were within 0.8-1.25-fold range. Estimated RIV metabolism via CYP3A4 was about 70% (50% liver, 20% gut) and < 20% via 2D6. Model projected increase in Cmax and AUC0-t by 1.2 and 1.5-fold, 1.5 and 2.3-fold, and 0.6 and 0.4-fold, with ranitidine, fluconazole, and efavirenz, respectively.

Conclusion: Validated PBPK model was applied to assess DDI potential and inform the DDI label in lieu of clinical studies.

1. Lukacova, V., et al., General Approach to Calculation of Tissue:Plasma Partition Coefficients for Physiologically Based Pharmacokinetic (PBPK) Modeling, in AAPS Annual Meeting. 2008: Atlanta, GA

2. Ding, J., et al., Metabolism and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor apatinib in humans. Drug Metab. Dispos. 41, 1195-210 (2013)