Population PK modeling and simulation to select a dosing schedule in Phase II trials for a novel TKI agent with time-dependent and nonlinear PK
Wang, X (1), Anak O (1), Saro J (1), Cramer J (1), Shi M (1), Zhou W (1), Angevin E (2), Escudier B (2), Schran H (1)
1Novartis Oncology, East Hanover , NJ, USA and Basel, Switzerland, 2Institut Gustave Roussy, Villejuif, France
Objectives: Compared to other TKI agents, TKI258 additionally targets FGFR. Over 2 fold of induction of plasma VEGF was observed at 500mg/day, FGF23 induction was observed at 400 mg/day. Significant reduction in Ktrans (DCE-MRI) also occurred at dose 400mg above. However, prolonged and over-proportional exposure was observed at dose 500mg and above following continuous daily dose. The objective of the analysis was to applying modeling and simulation to selecting a dosing schedule that can achieve higher but under controlled exposure for Phase II clinical trials.
Methods: TKI258 plasma concentrations from 93 patients following continuous daily dose were used for model development. Time-dependent PK resulted from enzyme induction was characterized by an indirect-response model; the over-proportional increases in exposure was described by inhibitory metabolism. Different dosing schedules were simulated with the model. A “5 days on/2 days off” intermittent dosing schedule that can achieve higher but under-controlled exposure was proposed and tested in a new dose escalation study (mRCC trial). Model predictions were compared with observed concentrations from mRCC trial. The final dosing schedule for phase II trials was then determined based on the exposure and tolerability from clinical trials following different dosing schedules. .
Results: The population PK model well described the TKI258 time ~ concentration across 25 to 600 mg daily. Volume of distribution was 2440 L, suggesting extensive extravascular distribution of drug. The EC50 for enzyme induction (0.3 ng/mL) agrees with the observed time-dependent decreasing in exposure at the lowest dose of 25mg/day. The baseline clearance of TKI258 was 56 L/h, whereas the maximum induced clearance could reach 3 times baseline value. The IC50 for inhibitory metabolism of TKI258 (170ng/mL) also explains that over-proportional increase in exposure occurs only at dose 400mg above (at 400mg daily dose, the median Cmax is < 200ng/mL). The observed plasma concentration of TKI258 from the mRCC trial agreed well with the model predictions. At both 500mg and 600mg dose levels, no prolonged accumulation of TKI258 was observed. Steady state was achieved in the 2nd week. Higher exposure during TKI258 administration following the intermittent dosing schedule was achieved, while the tolerability was improved..
Conclusions: The intermittent dosing schedule suggested from model simulation and confirmed by the mRCC trial was selected as the dosing schedule for Phase II pivotal trial.