Population pharmacokinetic (PK)/pharmacodynamic (PD) modeling and simulations for exposure‐;tumor response relationships: Motesanib in a phase II thyroid cancer (TC) trial

Abstract

e14528 Background: Motesanib is a highly selective, oral inhibitor of VEGF receptors 1, 2, and 3; PDGFR; and Kit that is being investigated for its antitumor activity. In a phase 2 monotherapy study, a response rate of 14% (per RECIST) was observed in patients (pts) with differentiated thyroid cancer (DTC; NEJM 359:31–42, 2008) compared with 1% in pts with medullary TC (MTC; Endocr Soc Ann Meeting 2007, abstract OR39–3). We evaluated the relationship between motesanib PK and tumor response, investigated whether differences in PK between MTC and DTC pts contributed to the observed difference in response, and simulated tumor response with different dose regimens in pts with TC. Methods: Data from the phase 2 TC trial were used for PK/PD modeling. The study enrolled 93 DTC and 91 MTC pts who received motesanib 125 mg once daily (QD). Motesanib concentrations were fitted to a 2- compartment population PK model. Estimates of pts’ PK parameters were used to calculate concentration and steady-state area under the curve values for motesanib, which were used as the exposure measures in population PK/PD modeling (ie, longitudinal exposure-tumor response modeling of drug effect on tumor growth dynamics). Monte Carlo simulations were used to evaluate the potential effect of doses other than 125 mg QD (75 mg and 100 mg QD) on tumor response in TC pts. Results: Clearance in MTC pts was 40% faster than in DTC pts (74 vs 44 L/h). The fit was significantly improved (P<0.001) when exposure instead of dose was used in the model. The exposure-tumor response model that incorporated the difference in exposure described change in tumor size well in both MTC and DTC populations. Clinical trial simulations using the preliminary model based on week 24 data predicted that DTC pts would achieve 19.7%, 15.7%, and 11.3% reductions in tumor size at week 24 following doses of 125 mg QD, 100 mg QD, and 75 mg QD, respectively. The actual change in median tumor size at week 24 following 125-mg QD dosing in DTC pts included in the PK/PD analysis was 17.9%. Conclusions: The use of 125 mg QD motesanib in DTC pts was supported by PK/PD modeling and Monte Carlo simulations. Differences in PK may explain the difference in tumor response observed in MTC and DTC patient populations. [Table: see text]