Abstract C83: Nonclinical in vitro ADME, disposition, and pharmacokinetic assessment of ARQ 092, a selective AKT inhibitor.
Authors: Volak Laurie P. , Bresciano Karen R. , Hall Terence , Vensel David , Lapierre Jean-Marc , Smukste Inese , McKearn David K. , Savage Ronald E. 
Published: August 2014

Abstract
Introduction: ARQ 092 is a potent and selective pan-AKT inhibitor currently in Phase 1 clinical studies for the treatment of advanced solid tumors. Here, we present preclinical in vitro drug-drug interaction, metabolism, disposition, and pharmacokinetic studies with ARQ 092.
Methods: ARQ 092 was assessed in vitro for cross-species metabolic stability; CYP450 (cytochrome P450) and UGT (UDP-glucuronosyltransferase) 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 092 to various tissues was measured after single and repeat dosing to mice as well as pharmacokinetics in mice, rats, and monkeys.
Results: Cross-species NADPH-dependent metabolism studies revealed that ARQ 092 metabolism was highly species dependent with ARQ 092 being most stable in rat and human liver microsomes (t1/2 &gt; 52 min) and least stable in mouse, dog, and monkey liver microsomes (t1/2 &gt; 13-33 min). Reaction phenotyping with CYP450 and UGT isozymes and CYP450 inhibitors/antibodies indicated that CYP2D6, CYP3A, UGT1A4, and possibly CYP2C9 are involved in ARQ 092 metabolism. ARQ 092 inhibited CYP2D6, 2C9, and 2C19 in HLM with IC50 values of 10.2, 3.0, and 4.0 µM, respectively, but had little activity against other isozymes tested; and no induction of CYP3A, 2B6, or 1A2 was observed. Based on these in vitro results, interactions with CYP3A4, 2D6, CYP2C9, or CYP2C19 substrates and/or inhibitors in the clinic are possible. Caco-2 and ATPase transporter studies showed that ARQ 092 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 of 23, 62, and 50% were determined in mice, rats, and monkeys, respectively, with half-lives ranging widely from 1.6 to 13.6 hrs with iv dosing and 4.3 to 16.6 hrs with po dosing. In mice, ARQ 092 was highly distributed to tissues with liver, lung, and kidney having the highest concentrations. This result correlates with the high volume of distribution of the compound in mice of 24.5 L/kg. In toxicokinetic studies, increases in Cmax and AUC were generally greater than dose proportional with repeat dosing and accumulation was observed in rats but not monkeys.
Conclusion: Collectively, these data indicate that ARQ 092 has sufficient oral bioavailability to advance into clinical testing. However, the potential for drug-drug interactions with ARQ 092 in the clinic will need to be investigated further. Additionally, careful selection of dosing regimens for ARQ 092 may be crucial based on the high volume of distribution and accumulation observed preclinically.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C83.
Citation Format: Laurie P. Volak, Karen R. Bresciano, Terence Hall, David Vensel, Jean-Marc Lapierre, Inese Smukste, David K. McKearn, Ronald E. Savage. Nonclinical in vitro ADME, disposition, and pharmacokinetic assessment of ARQ 092, a selective AKT 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 C83.