Background: An oral tetra-arsenic tetra-sulfide (AS₄S₄) formula has been recommended as an outpatient post-remission treatment for Chinese adults with acute promyelocytic leukemia (APL) but limited data are available for children. In this exploratory study, we aimed to evaluate the pharmacokinetics and safety of the AS₄S₄ formula in children.
Methods: Eleven newly diagnosed and one relapsed pediatric patient (4– 14 years of age) treated with the AS₄S₄ formula were included. Blood samples were collected from 12 children, and drug concentrations were quantified by ICP-MS. Population pharmacokinetic analysis and Monte-Carlo simulation were performed using NONMEM software. Toxic effects were graded according to the NCI-CTCAE, Version 3.
Results: A total of 107 arsenic concentrations (0.1– 75.0 μg L^{− 1}) were used for population pharmacokinetic analysis. The median (range) of estimated weight-normalized CL and volume distribution at steady-state were 45.26 (35.63– 82.18) L h^{− 1} kg^{− 1} and 230.37 (85.96– 495.68) L kg^{− 1}, respectively. No patients discontinued AS₄S₄ treatment owing to adverse events, and there were no drug-related adverse events over grades 3– 4. All newly diagnosed APL patients were in MCR with a median follow-up of 28 months (range, 23 to 37 months). Both the estimated 3-year EFS and OS rates were 100%.
Conclusion: The pharmacokinetics and safety oral AS₄S₄ formula was evaluated for the first time in pediatric APL. The pharmacokinetic assessment demonstrated that the dosing regimen of 60 mg/kg/d TID resulted in a higher steady-state through concentration in children than that which was achieved in adults. The results of this study indicate that the AS₄S₄ formula is safe in newly diagnosed pediatric APL patients.
Keywords: acute promyelocytic leukemia, Realgar-Indigo Naturalis Formula, pediatric, safety, population pharmacokinetics