Pharmacokinetics of Arsenic Species with Relapsed or Refractory Acute Promyelocytic Leukemia (APL) Treated with Arsenic Trioxide (ATO) in Japanese Patients.

Abstract Background: The therapy with ATO induced high complete remission and maintained for long survival for patients with relapsed or refractory APL. While the clinical effect of ATO against APL was confirmed, its pharmacokinetics has yet to be clarified. In most reports on pharmacokinetics of ATO, the arsenic concentrations were measured as total arsenic. We investigated the pharmacokinetics of arsenic species in Japanese patients with relapsed or refractory APL treated with ATO. Patients and Methods: In the prospective study, from 12 patients with APL treated with ATO, the blood and urine for the pharmacokinetic data were collected and subsequently stored frozen until analysis. ATO (0.15 mg/kg) was intravenously administered once daily over 2 hours to until bone marrow remission to a maximum of 60 days. The plasma and urine were collected on day 1 and after 1, 2 and 4 weeks. Inorganic arsenic (AsIII and AsV) and the major metabolites monomethylarsonic acid (MAAV) and dimethylarsinic acid (DMAAV) in plasma and urine were quantified by HPLC/ICP-MS. Results: Ten of 12 patients (83%) achieved complete remission (CR). Six of ten (60%) who achieved CR were negative in the post-treatment RT-PCR test. For two patients the blood and urine were collected also during consolidation. The plasma concentrations of inorganic arsenic on day 1 reached the Cmax (mean 22.6±11.4 ng/mL) immediately after completion of administration followed by a biphasic elimination while the appearance of methylated metabolites in the blood was delayed. During the repeated administration, the plasma concentrations of inorganic arsenic reached the steady-state. The Cmax of inorganic arsenic on week 4 was similar (mean 23.2±10.2 ng/mL) but the elimination was delayed. As a result, the AUC increased about 2-fold (from mean 211.8±55.1 to 474.8±192.6 ng/mL), and the clearance declined (from 0.7±0.2 to 0.4±0.1 L/kg/h) but no marked change was observed in volume of distribution. In contrast, the MAAV and DMAAV concentrations increased in relation to increased administration frequency fold (from mean 3.1±1.6, 5.4±2.9 to 10.9±4.7, 21.4±12.3 ng/mL). The plasma concentrations of arsenobetaine, an organic arsenic compound derived from seafood, remained almost constant (about 2 mg/mL) during the study period. The urinary excretion rates of AsIII and AsV remained almost constant after week 1, suggesting that the steady-state was attained. In contrast, a tendency to increase with administration frequency was observed in the excretion rates of MAAV and DMAAV after week 4 (from mean 17.4±11.2, 19.4±8.5 to 19.6±10.0, 21.1±9.5 %). The total arsenic excretion rate remained at ~60% of dose after week 1. Conclusion: ATO is metabolized when administered intravenously to APL patients and methylated metabolites were promptly eliminated from the blood and excreted into urine after completion of administration, indicating no measurable accumulation of ATO in the blood.