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29.05.2018 | Original Article | Ausgabe 2/2018

Cancer Chemotherapy and Pharmacology 2/2018

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

Zeitschrift:
Cancer Chemotherapy and Pharmacology > Ausgabe 2/2018
Autoren:
Chunlu Gao, Shuang Hu, Meihua Guo, Xin Hai, Jin Zhou
Wichtige Hinweise
Chunlu Gao and Shuang Hu contributed equally to this work.

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 (AsIII) and its metabolites, monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV), 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. MMAV/iAs increased and remained stable at value about 0.6 after day 4, while DMAV/MMAV declined under 2 after day 4. Compared with 2 h infusion, clearance (CL) of AsIII was significantly lower (0.8 ± 0.2 vs. 2.7 ± 1.7 L/kg/h, P = 0.002) while AUC0–t of AsIII 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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