ALLG APML5: Bioavailability and safety of oral arsenic trioxide assessed during consolidation therapy for APL

Abstract

The prognosis for patients with acute promyelocytic leukemia (APL) has improved dramatically since the introduction of all-trans retinoic acid (ATRA) and intravenous arsenic trioxide (ATO). However, ATO administration requires daily infusions over several months, representing an onerous burden for hospitals and patients. We evaluated the bioavailability of a novel encapsulated oral ATO formulation in APL patients in first complete remission during standard-of-care consolidation. After a pilot study exploring the likely oral dose requirement, total arsenic pharmacokinetics were evaluated in 20 patients after both intravenous and oral ATO 0.15 mg/kg/d, with exposure to oral ATO restricted to the first week in 2 of the 4 ATO cycles. The primary endpoint was bioequivalence of area under the curve from 0-24 hours (AUC0-24), with bioequivalence of maximum concentration achieved (Cmax) as the key secondary endpoint. The 90% confidence intervals (CI) around point estimates of the geometric means of the oral/intravenous ratios for AUC0-24 and Cmax were compared with bioequivalence limits specified by the European Medicines Agency (0.80-1.25). The estimated oral/intravenous ratios and 90% CI for AUC0-24 in whole blood and plasma were 0.993 (0.954-1.034) and 1.030 (0.977-1.087) respectively; data for Cmax also satisfied bioequivalence requirements. Exploratory studies of arsenic species in plasma showed bioequivalence for AUC0-24 with As(III) (oral/intravenous ratio 0.966 (0.879-1.063)). The adverse event profiles of oral and intravenous ATO were comparable for cycles commencing with the IV and oral formulations. In conclusion, this novel oral ATO formulation is bioequivalent with intravenous ATO and offers a convenient alternative for patients with APL. Accession Number: ACTRN12616001022459.