Abstract C84: Nonclinical metabolism, disposition, pharmacokinetics, and in vitro drug-drug interaction assessment of ARQ 087, a pan-FGFR inhibitor.

Abstract

Abstract Introduction: ARQ 087 is a potent multi-tyrosine kinase inhibitor with activity against the FGFR family currently in Phase I clinical studies for the treatment of advanced solid tumors. Here, we present preclinical metabolism, disposition, pharmacokinetic and in vitro drug-drug interaction studies with ARQ 087. Methods: ARQ 087 was assessed in vitro for cross-species metabolic stability; CYP450 (cytochrome P450) reaction phenotyping; CYP450 inhibition/induction; Caco-2 absorption and efflux; and P-gp (P-glycoprotein), BCRP (Breast Cancer Resistance Protein), and MRP2 (Multidrug Resistance-associated Protein 2)-mediated ATPase stimulation. Distribution of ARQ 087 to various tissues was measured after single and repeat dosing to mice as well as pharmacokinetics in mice, rats, and dogs. Results: Cross-species NADPH-dependent metabolism studies revealed that ARQ 087 undergoes little, if any, NADPH-dependent metabolism in human, rat, dog, mouse, and monkey microsomes. Half-lives generally exceeded 60 minutes, with little or no variation observed between gender and species tested. Reaction phenotyping with CYP450 and CYP450 inhibitors/antibodies indicated that ARQ 087 was generally stable against all CYP450 isoforms tested (1A2/3A4/2C9/2C19/2D6/2C8). Average half-lives against all isoforms were greater than 50 minutes. ARQ 087 showed no significant potential to inhibit CYP3A4, 2C19, 2C8, or 2C9, with average IC50s greater than 20 µM. Some inhibition of CYP1A2, and 2D6 was observed in HLM, with IC50 values of 12 and 19 µM respectively. ARQ 087 did not induce CYP3A4 or 1A2, however concentrations of 1 µM or greater did appear to induce CYP2B6 in cells from one of three individuals tested. Based on these in vitro results interactions with CYP2B6 substrates and/or inhibitors in the clinic are possible. Caco-2 and ATPase transporter studies showed that ARQ 087 was highly permeable with little efflux in Caco-2 monolayers but may be an inhibitor/substrate of P-gp and mutant BCRP. Oral bioavailability values were determined to be 32% - 46% in mice, rats, and dogs. The elimination half-lives following intravenous administration were 2.1, 5.9, and 9.0 hrs in mice, rats, and dogs, respectively. Flip-flop pharmacokinetic profiles following oral administrations in mice and rats were observed, but not in dogs. Moderate systemic clearance were observed in all 3 species with hepatic extraction ratio ranging from 40% - 70%. Conclusion: Collectively, these data indicate that ARQ 087 has sufficient oral bioavailability to advance into clinical testing. There appears to be a low likelihood, with the possible exception of CYP2B6 substrates, of drug-drug interactions based on Phase I metabolism. However, the high degree metabolic stability along with the potential to accumulate in tissues/organs observed in preclinical testing suggests that careful selection of dosing regimens for ARQ 087 will be crucial to maximize patient benefit. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C84. Citation Format: Terence G. Hall, Laurie P. Volak, Karen R. Bresciano, Yunxia Wang, Chang-Rung Chen, Syed Ali, David Mckearn, Inese Smukste, Ronald E. Savage. Nonclinical metabolism, disposition, pharmacokinetics, and in vitro drug-drug interaction assessment of ARQ 087, a pan-FGFR inhibitor. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C84.