ALLG APML5: a comparative bioavailability study of encapsulated oral arsenic trioxide and intravenous arsenic trioxide in patients with acute promyelocytic leukemia undergoing consolidation therapy

H. Iland, J. Reynolds, A. Boddy, L. Khoo, S. Yuen, R. Gasiorowski, S. Lane, A. Wei, R. Harrup, P. Marlton, C. Risteski

Research output: Contribution to journalMeeting abstractpeer-review

Abstract

Background: The combination of all-trans retinoic acid (ATRA) and intravenous arsenic trioxide (IV ATO) cures most patients with acute promyelocytic leukemia (APL). However, daily 2-hour infusions of ATO over several months constitute a significant burden for hospitals and patients. A novel encapsulated formulation of oral ATO (Phebra Pty Ltd, Australia) has the potential to significantly simplify treatment delivery and improve the overall treatment experience of patients with APL. Aims: To characterize the bioavailability of encapsulated oral ATO in patients with APL by comparing the AUC0–24 and Cmax of total arsenic in whole blood (WB) and plasma (PL) after oral and IV ATO administration. Methods: ALLG APML5 (ACTRN12616001022459) is a bioavailability study embedded within a standard-of-care consolidation regimen. Eligibility required documented hematological complete remission following induction with ATRA + IV ATO (+ idarubicin for patients with initial WBC count > 10x109/l). Registered patients were consolidated with 7 cycles of ATRA 45 mg/m2/d (7d/week for 2 weeks, with 2 weeks between cycles), and 4 cycles of IV ATO 0.15 mg/kg/d (5d/week for 4 weeks, with 4 weeks between cycles). Pharmacokinetic (PK) sampling was performed on days 1 and 4 in week 1 of each ATO cycle. Oral ATO 0.15 mg/kg/d (administered 1 hour before food as 10 mg and/or 1 mg capsules rounded up to the nearest 1 mg) was substituted for IV ATO in week 1 of cycle 2, and again in week 1 of cycle 4 (with PK-directed dose modification if required). Total arsenic was quantitated by inductively coupled plasma mass spectrometry. Point estimates of mean oral/IV arsenic ratios ± 90% confidence intervals (CI) for AUC0–24 and Cmax in WB and PL were calculated by linear mixed model analysis incorporating fixed and random effects, and the results were compared with conventional bioequivalence limits (0.80, 1.25). Results: This preliminary analysis encompasses 53 evaluable PK profiles from 9 patients: 4 males, 5 females, median age 52 years (range 20–66). Both formulations were associated with significant increases in all PK parameters from day 1 to day 4 (p 
Original languageEnglish
Article numberPS1028
Pages (from-to)463-464
Number of pages2
JournalHemaSphere
Volume3
Issue numberS1
DOIs
Publication statusPublished - 2019
Externally publishedYes
Event24th Congress of the European Hematology Association - Amsterdam, Netherlands
Duration: 13 Jun 201916 Jun 2019

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