Dasatinib (BMS-354825) pharmacokinetics correlate with pSRC pharmacodynamics in phase I studies of patients with cancer (CA180002, CA180003)
3046 Background: Dasatinib - an inhibitor of several oncologenic kinases including BCR-ABL and SRC - has demonstrated efficacy in CML and Ph+ ALL, and is being evaluated in patients with solid tumors. Studies CA180–002, and CA180–003 were multiple ascending dose studies of dasatinib in patients with refractory Ph+ leukemia, and solid tumors, respectively. We have analyzed the preliminary results of pharmacokinetics (PK) and pharmacodynamic (PD) biomarker phospho-SRC (pSRC) combined across the CA180002 and CA180003 studies. Methods: Dasatinib was administered orally at doses of 15 - 180 mg QD or 25 - 160 mg BID. Dasatinib PK was determined by LC MS/MS. The level of phospho-SRC in peripheral blood mononuclear cells (PBMCs) was determined by an ELISA and was used as a surrogate biomarker of the level of kinase activity of the SRC family members. PK-PD modeling was performed using a two-compartment PK model with first-order absorption kinetics and an indirect inhibitory Emax model as the PD model. Results: On the BID regimen, pSRC inhibition was approximately dose-dependent across the dosing range. Inhibition also appeared to be directly correlated with dasatinib plasma concentration, with maximal inhibition achieved at ∼2.5 hr. Based on PK-PD modeling, the estimated EC50 (the plasma concentration required to achieve 50% inhibition of pSRC) is 14.4 ng/mL. Conclusions: SRC family kinase activity is substantially inhibited at the exposures of dasatinib achieved to date. The optimal regimens of dasatinib to achieve both target inhibition and solid tumors efficacy will be determined based on biomarkers, clinical responses, and toxicity profiles. [Table: see text]