Abstract 750: Impairment of clofarabine (CLO) clearance (CL) in the presence of cimetidine: Evidence of a drug-drug interaction between clofarabine and inhibitors of human organic cation transporter-2 (hOCT2)

Background: CLO is a nucleoside analog with efficacy in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Preclinical studies using an isolated, perfused rat-kidney model suggested that CLO may be a substrate of OCT2, a channel that mediates the transport of cations across the renal tubular basolateral membrane. Evidence of this mechanism is lacking in humans, though this property could contribute to drug interactions with compounds such as cimetidine that inhibit hOCT2. Methods: Eligible patients were: 1) untreated AML ≤ 60 years of age unsuited for intensive induction therapies, 2) relapsed or refractory AML, or 3) MDS patients who failed ≤ 1 prior regimen. Patients were treated with CLO according to the schedule: CLO 15 mg/m2 IV day 1, CLO 30 mg/m2 PO day 3, CLO 15 mg/m2 IV day 5 preceded by two doses of oral cimetidine (800 mg PO 8-10 hours apart), and CLO 30 mg/m2 PO on days 6 and 7. Pharmacokinetic (PK) studies were obtained after CLO dosing on days 1, 3 and 5. CLO plasma concentration was determined, and concentration-time data was analyzed by non-compartmental methods. Oral bioavailability (F) was determined for each patient. The geometric means of area under the curve, 0-infinity (AUC), and CL for intravenous CLO administered after cimetidine doses were compared with AUC and CL for intravenous CLO administered without cimetidine. Results: To date, 8 patients have been treated. Mean F = 0.66, 90% confidence interval (CI) (0.49, 0.87). Comparisons of PK parameters between IV dosing with and without cimetidine are shown in the table. Conclusions: Co-administration of the hOCT2 inhibitor cimetidine with CLO appears to increase CLO AUC by impairing renal CL. Enrollment continues in an attempt to further support the putative mechanism of CLO renal clearance by hOCT2-mediated tubular secretion, and to further investigate the clinical import of this drug-drug interaction. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 750. doi:1538-7445.AM2012-750