Pharmacokinetics- and Pharmacodynamics-Guided Optimization of the Dose and Treatment Schedule for the Dual SRC/ABL Inhibitor BMS-354825.
Authors: Luo Feng Roger , Yang Zheng , Camuso Amy , Smykla Richard , Castenada Stephen , Flefleh Christine , Fager Krista , Inigo Ivan , Kan David , McGlinchey Kelly , Wen Mei-Li , Wild Robert , Borzilleri Robert , Lombardo Louis , Kramer Robert , Lee Francis Y. 
Published: October 2019

Abstract
Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) originates from multipotential stem cells and is caused by a reciprocal translocation between chromosomes 9 and 22, resulting in the formation of the fusion protein BCR-ABL, a constitutively activated tyrosine kinase. The discovery of imatinib, which selectively targets BCR-ABL, represents a breakthrough treatment for this disorder. However, emerging evidence indicates that a significant proportion of patients in the early chronic phase of the disease fail to achieve optimal response to imatinib due to innate or acquired drug resistance. Moreover, patients in the accelerated or blast crisis phases of the disease in general respond far less favorably to imatinib therapy. There is an urgent need for improved treatment options for these patient populations. BMS-354825, a dual-selective inhibitor of SRC and ABL kinases has demonstrated promising antileukemic activity in vitro and in vivo against preclinical models of human CML, including several that were resistant to imatinib through a variety of mechanisms (Lee et al., Proceedings of the AACR, 2004; Donato et al., Proceedings of the AACR, 2004; Shah et al., Science, 16:399–401, 2004). BMS-354825 is currently being evaluated in a Phase I clinical trial. We performed studies to gain better understanding of the relationship between the pharmacokinetics (PK) and pharmacodynamics (PD) of BMS-354825 and its antileukemic activity. Efficacy was determined in a human CML model (K562) grown subcutaneously in mice. Mouse plasma PK was determined by liquid chromatography/mass spectrometry. Inhibitions of the phosphorylation of tumoral BCR-ABL and its down-stream substrate CrkL, were used as PD markers and were measured by Western blot analysis. BMS-354825 administered orally was efficacious (curative) over a wide range of doses (1.25–50 mg/kg/dose) and exhibited predictable and dose-dependent pharmacokinetics. The time-course of tumoral BCR-ABL and CrkL inhibition and recovery directly correlated with plasma level of BMS-354825. At the minimum effective dose of 1.25 mg/kg/dose, maximum inhibition of BCR-ABL was observed at ~3 hr post-dose, and the inhibition was partially reversed at 7 hr and completely recovered between 7–17 hr post-dose. Based on these data, a PK/PD model was established which predicted that the plasma concentration of BMS-354825 required to effectively inhibit BCR-ABL in K562 cells was ~20 nM. In addition, the model predicted that at a given total dose, twice-a-day split-dose regimens should be more efficacious than once-a-day regimens. This was supported by in vivo efficacy studies in K562 xenografts where BMS-354825 was curative at 1.25 mg/kg/dose when administered twice-a-day, whereas once-a-day dosing required 5 mg/kg/dose to achieve the same response. In summary, BCR-ABL and/or CrkL phosphorylation in CML cells can serve as in vivo PD markers for BMS-354825. The safety/efficacy of BMS-354825, administered either once daily or twice-a-day, is currently being evaluated in Phase I clinical trials in CML patients.