Population pharmacokinetic (PopPK) and exposure-response (ER) modeling of cabozantinib (C) in patients (pts) with renal cell carcinoma (RCC) in the phase 3 METEOR study.

2565Background: PopPK and ER models were developed to characterize the C concentration-time profile and the relationship between C exposure and efficacy endpoints in pts with RCC. Methods: The PopPK model was developed using nonlinear mixed effects modeling methodology (NONMEM v7.3) and incorporated 1650 measurable PK concentrations from 63 healthy volunteers (HV) and 282 pts with RCC. An extensive PK sampling strategy was employed for HV whereby C was administered as a single 20, 40 or 60 mg dose, while a single steady-state sample was collected at Day 29 and Day 57 for RCC pts initially receiving 60 mg C qd. Time-to-event Cox proportional hazard ER models were developed to characterize the relationship between various individual predicted C exposure measures and the relative hazard for specified efficacy endpoints including progression-free survival (PFS). Results: A 2-compartment model with first-order elimination and two parallel (fast and slow), lagged first-order absorption processes adequately desc...