e13074 Background: Clofarabine (CLO) is a purine analog with activity in myeloid neoplasms. Its oral dosing has been based on an estimated bioavailability (F) of 49% from uncontrolled trials. Animal models suggest that CLO renal clearance (CL) may be impaired in the presence of inhibitors of organic cation transporter-2 (OCT2), which mediates transport across the renal tubular basolateral membrane. We conducted a pharmacokinetic (PK) study of CLO to determine F, and examine the effect of the OCT2 inhibitor, cimetidine (CIM) on intravenous (IV) CLO. Methods: Patients had: 1) untreated AML ≥ 60 years of age unsuited for standard induction, 2) relapsed or refractory AML, or 3) MDS after failure of ≥ 1 prior regimen. Treatment was: CLO 15 mg/m2 IV day 1, CLO 30 mg/m2 orally (PO) day 3, CLO 15 mg/m2 IV day 5 preceded by two doses of oral CIM, and CLO 30 mg/m2 PO on days 6 and 7. PK studies were obtained after CLO dosing on days 1, 3 and 5. For each dose, CLO plasma concentration was determined, and concentration-time data was analyzed by non-compartmental methods. F was determined for each patient. The geometric means of area under the curve (AUC), 0-∞, and CL for IV CLO administered after CIM doses were compared with AUC and CL for IV CLO administered without CIM. Results: Interim data for the first ten treated patients, with comparisons of PK parameters are shown in the table below. Conclusions: Using patients as their own controls, F of CLO is higher than previously estimated. AUC of CLO is increased and CL is decreased in the presence of CIM, likely owing to inhibition of OCT2-mediated renal tubular secretion. This study is the first human trial to suggest that CLO CL may be impaired in the presence of OCT2 inhibitors, such as cimetidine, trimethoprim, verapamil and nicotine. [Table: see text]
Renal secretion of hydrochlorothiazide involves organic anion transporter 1/3, organic cation transporter 2, and multidrug and toxin extrusion protein 2-K
