https://orcid.org/0000-0002-1830-338X
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Abstract
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.
Acknowledgments
We thank all of the patients who participated in this study and all of the participants and research staff in our hospital. We thank the AIYOU and SHENHUA foundations for their financial support for our study of leukemia in children.
Data Sharing Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher. The data can be shared by emailing requests to the corresponding author Prof.Dr. Wei Zhao or Prof.Dr. Xiao-Fan Zhu.
Ethics Approval
All procedures performed in studies involving human participants were approved by the Ethics Committee of the Institute of Hematology & Blood Diseases Hospital and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Consent to Participate
Signed informed consent was obtained from the patients’ parents or guardians.
Clinical Trial Registry
This trial was registered in the Chinese Clinical Trial Registry (ChiCTR-OIC-16010014).
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
Li Zhang, Xin-Mei Yang, Jing Chen, Lei Hu, Fan Yang, Yue Zhou, Bei-Bei Zhao, Wei Zhao and Xiao-Fan Zhu declare that they have no conflicts of interest relevant to this article to disclose.