PHARMACOKINETIC STUDY OF ORAL AND BOLUS INTRAVENOUS 2-CHLORODEOXYADENOSINE IN PATIENTS WITH MALIGNANCY

Purpose: This study was designed to evaluate the absolute bioavailabil ity (F value) of 2-chlorodeoxyadenosine (cladribine; 2-CdA) after mult iple oral administrations, and the intersubject variability after oral and 2-hour intravenous (IV) administration schedules in patients with malignancy. Patients and Methods: Patients with advanced malignancies were eligible. There were two treatment cycles; during cycle 1, patie nts received 2-CdA solution at 0.28 mg/kg/d orally under fasting condi tions for 5 consecutive days concomitantly with omeprazole, and 4 week s later during cycle 2 patients received 2-CdA as a 2-hour IV infusion of 0.14 mg/kg/d for 5 consecutive days. Serial blood samples for 2-Cd A plasma levels were obtained after drug administrations on days 1 and 5 during each treatment cycle. Results: Ten patients completed cycles 1 and 2,. The F value of oral 2-CdA measured on days 1 and 5 was 37.2 % and 36.7%, respectively. For both oral and IV multiple administratio ns, there was no significant accumulation in maximum concentration (C- max), and the intersubject variabilities (coefficient of variation [CV ], similar to 40%) in C-max and area under the concentration-time curv e from 0 to 24 hours [AUC((0-24))] values were comparable for both rou tes on days 1 and 5. A three-compartment open model was applied to the plasma concentration data after oral and IV administrations and resul ted in good agreement between observed and simulated concentration-tim e profiles. Neutropenia was the principal adverse event observed when 2-CdA was administered orally and IV. Conclusion: The F value of 2-CdA after oral administration was approximately 37% and there were no cum ulative differences in bioavailability observed on multiple dosing of the drug. The absorption and disposition characteristics of oral 2-CdA were linear and predictable with this dosing regimen. (C) 1996 by Ame rican Society of Clinical Oncology.