Pharmacokinetics and cardiac impact of arsenic trioxide (ATO) oral solution (SDK001) under fasting, fed, and calcium carbonate co-administration conditions compared with intravenous ATO in patients with acute promyelocytic leukemia

Abstract

Abstract Background Arsenic Trioxide (ATO) is a crucial component of the treatment of Acute Promyelocytic Leukemia (APL), with frontline use in combination with all-trans retinoic acid (ATRA) resulting in >90% cure rate. In most countries, ATO is only available as an intravenous (IV) preparation. An oral formulation of ATO is approved in Hong Kong where it has been used for two decades in APL, leading to cure rates similar to IV-ATO. Advantages of oral-ATO include ease of administration, improved cardiac safety, and reduced hospitalization, all of which decrease patient and provider burden, as well as healthcare costs. Here, we describe the results of a randomized, open label, single-dose, 4-period, 4-treatment cross-over study in APL patients, to evaluate the Pharmacokinetics (PK) and safety of oral-ATO (SDK001) under fasting and fed conditions compared with IV-ATO, and to evaluate interactions with calcium carbonate, as divalent salts (e.g., Ca2+) could form insoluble complexes with arsenic and reduce oral bioavailability. Methods The study population included newly diagnosed APL patients ≥18 years old in first remission after induction and consolidation with ATO. Other key inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1; and adequate organ function. Key exclusion criteria included significant arrhythmia, cardiac conduction disorders, corrected QT interval using Fridericia's formula (QTcF) of >450 msec for men or >460 msec for women; and recent symptomatic congestive heart failure. Patients were randomized 1:1:1:1 to one of the four treatment sequences with a 7-day washout between periods. The four treatment groups were 0.15 mg/kg IV-ATO (A), 0.15 mg/kg SDK001 under fasting condition (B), fed condition (C), and with 1 g calcium carbonate (D). The primary endpoints included systemic exposure (AUCinf) and peak plasma concentration (Cmax) of Arsenite (AsIII) for the comparison of SDK001 versus IV-ATO under fasting; AUCinf and Cmaxof AsIII, for the comparison of SDK001 under fasting versus fed conditions; and AUCinf and Cmaxof AsIII, for the comparison of SDK001 with or without calcium carbonate under fasting. Change of QTcF interval between baseline and 2 hours after dosing was also evaluated in all treatment groups. Results Twelve patients (median age: 55 years; range: 23-71) completed all four treatment periods at the University of Hong Kong. AUCinf of AsIII following SDK001 under fasting was comparable with that of IV-ATO. The geometric mean ratios (GMR) of AUCinf and Cmax (SDK001 fasting versus IV-ATO) were 107.4% (90% confidence interval, CI: 99.3–115.5%) and 69.2% (90% CI: 61.1–77.3%), respectively. Comparison of SDK001 under fed versus fasting conditions showed no food effect on systemic exposure, with an AUCinf ratio of 95.6% (90% CI: 88.6–102.6%). However, Cmax was reduced by food intake, with a GMR of 61.0% (90% CI: 53.9–68.0%), indicating a prolonged absorption rate under fed conditions. Co-administration of SDK001 with calcium carbonate under fasting had no impact on AsIII pharmacokinetics. The AUCinf ratio (with versus without calcium carbonate) was 102.9% (90% CI: 94.7–111.0%) and the Cmax was 101.6% (90% CI: 93.4–109.8%), confirming the absence of this drug-drug interaction. Cardiac safety parameters showed the mean increase from baseline in QTcF 2 hours after dosing was higher for IV-ATO (12.7 msec; 90% CI: 9.1–16.3 msec) than SDK001 under fasting (7.6 msec; 90% CI: 4.5–10.7 msec) and fed conditions (-2.7 msec; 90% CI: -7.6–2.1 msec). No Grade ≥ 3 adverse events or SAEs were reported in this study, and no AEs led to treatment discontinuation. Conclusion Results from SDKARS-101 support further investigation of SDK001 in a Phase 3 trial as a more convenient and potentially safer alternative to IV-ATO for the treatment of APL patients. SDK001 achieved systemic arsenic exposure comparable to IV-ATO, but with a lower Cmax, especially under fed conditions. No drug-drug interaction was observed with calcium carbonate. The risk of QTcF prolongation was attenuated with SDK001 compared with that of IV-ATO, which was further reduced with food.