Clinical pharmacokinetics and safety profile of single agent arsenic trioxide by continuous slow-rate infusion in patients with newly diagnosed acute promyelocytic leukemia

Abstract

Purpose

This study evaluated pharmacokinetics (PK) and safety profiles of single agent arsenic trioxide (ATO, As₂O₃) administrated as continuous slow-rate infusion in patients with newly diagnosed acute promyelocytic leukemia.

Patients and methods

Patients received 0.16 mg/kg ATO per day. ATO was given for 40 min infusion on the first day followed by 18–20 h daily at a very slow rate with infusion speed of 8 drips/min. During the first week, plasma samples were collected immediately before next administration on each day, and 0.5, 1, 2, 4, 8, 12 h after administration, at the end of infusion (18 h) on day 7. Total arsenic was determined by ICPMS. Arsenic species, arsenious acid (As^III) and its metabolites, monomethylarsonic acid (MMA^V) and dimethylarsinic acid (DMA^V), were quantified by UHPLC-ICPMS. Safety assessment and PK analysis was conducted.

Results

Hyperleukocytosis occurred in two patients and no severe toxicity was observed. Total arsenic gradually accumulated from 15.84 to 34.12 ng/mL during the first week of therapy. MMA^V/iAs increased and remained stable at value about 0.6 after day 4, while DMA^V/MMA^V declined under 2 after day 4. Compared with 2 h infusion, clearance (CL) of As^III was significantly lower (0.8 ± 0.2 vs. 2.7 ± 1.7 L/kg/h, P = 0.002) while AUC_0–t of As^III was significantly increased (213.9 ± 38.6 vs. 82.6 ± 55.7 L/kg/h, P = 0.028).

Conclusion

Continuous slow-rate ATO infusion provided an alternative administration for ATO therapy with few toxic effects. Degree of methylation from MMA to DMA is inconsistent with that from iAs to MMA. PK of arsenic species is considered important for clinical use of ATO.

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