Abstract 4630: Population pharmacokinetic-pharmacodynamic (PPD) modeling of masitinib administered in combination with gemcitabine to pancreatic cancer patients
Authors: Rezai Keyvan , Urien Saik , Weill Sophie , Barbin Lise , Moussy Alain , Lokiec François 
Published: May 2015

Abstract
Background: Masitinib is a tyrosine kinase inhibitor that targets wild-type and mutant forms of c-Kit, as well as PDGFR, Lyn, and Fyn kinases. Masitinib in combination with gemcitabine has been shown to produce a clinically relevant survival benefit in first-line treatment of advanced pancreatic cancer. This efficacy is most likely due to its inhibition of mast cell activity and the stimulation of an anti-tumoral immune response via macrophages. The objectives of this study were to assess masitinib pharmacokinetics (PK) and pharmacodynamics (PD), and to perform a POP-PK/PD modeling of masitinib in patients with advanced pancreatic cancer.
Materials and Methods: Treatment naïve pancreatic cancer patients received oral masitinib at 9 mg/kg/day b.i.d. in combination with standard gemcitabine treatment. For PK analysis, 6 time-point blood samples were collected on D1 and D14 of the first cycle. POP-PK analyses were carried out using the nonlinear mixed effect modeling software program Monolix. Constant residual variability and exponential between subject variabilities (BSVs) were used. Different covariates including body weight (BW) and sex were investigated. PK parameters were allometrically normalized for BW to a 70 kg individual. A PPD analysis was performed to adequately describe myelosuppression time courses in terms of masitinib PK. The individual PK parameters were used to generate individual masitinib concentrations and served to model the inhibitory effect of masitinib on absolute neutrophil count (ANC).
Results: For 22 patients (9 male and 13 female), 264 time-plasma concentrations and 89 ANC were available for analysis. A 2-compartment open model with linear elimination adequately described the masitinib PK. The BSVs could be well estimated for all structural parameters (i.e. absorption constant, Ka; clearance, CL; volume of distribution, V1; and inter-compartmental clearances, Q) with the exception of peripheral volume V2. The main PK parameters (RSE%) estimated for masitinib were: Ka=0.179 (20%) h-1, CL=66.4 (16%) L/h, Q=52.7 (25%) L/h, V1=179 (24%) L, and V2=928 (22%) L. The main covariate effects were related to BW, which influenced all PK parameters, and to albumin, which influenced CL. The mean IC50 estimated for an inhibitory effect of masitinib on ANC was very high at 2210 µg/L.
Conclusions: The POP-PK modeling satisfactorily described the plasma masitinib time-concentration curves in pancreatic cancer patients. Clearance of masitinib increased with increasing total BW and albumin. A central volume higher than the circulating blood volume and a large volume of the deep compartment suggest that masitinib has large tissue diffusion. PPD modeling demonstrates that the hematotoxic effect of masitinib for ANC is very small and the feedback for the stimulation of ANC in response to masitinib plus gemcitabine treatment is strong.
Citation Format: Keyvan Rezai, Saik Urien, Sophie Weill, Lise Barbin, Alain Moussy, François Lokiec. Population pharmacokinetic-pharmacodynamic (PPD) modeling of masitinib administered in combination with gemcitabine to pancreatic cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4630. doi:10.1158/1538-7445.AM2014-4630