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      Population Pharmacokinetics and Safety of Oral Tetra-Arsenic Tetra-Sulfide Formula in Pediatric Acute Promyelocytic Leukemia

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          An oral tetra-arsenic tetra-sulfide (AS 4S 4) 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 AS 4S 4 formula in children.


          Eleven newly diagnosed and one relapsed pediatric patient (4–14 years of age) treated with the AS 4S 4 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.


          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 AS 4S 4 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%.


          The pharmacokinetics and safety oral AS 4S 4 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 AS 4S 4 formula is safe in newly diagnosed pediatric APL patients.

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          Most cited references 21

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          Computing normalised prediction distribution errors to evaluate nonlinear mixed-effect models: the npde add-on package for R.

          Pharmacokinetic/pharmacodynamic data are often analysed using nonlinear mixed-effect models, and model evaluation should be an important part of the analysis. Recently, normalised prediction distribution errors (npde) have been proposed as a model evaluation tool. In this paper, we describe an add-on package for the open source statistical package R, designed to compute npde. npde take into account the full predictive distribution of each individual observation and handle multiple observations within subjects. Under the null hypothesis that the model under scrutiny describes the validation dataset, npde should follow the standard normal distribution. Simulations need to be performed before hand, using for example the software used for model estimation. We illustrate the use of the package with two simulated datasets, one under the true model and one with different parameter values, to show how npde can be used to evaluate models. Model estimation and data simulation were performed using NONMEM version 5.1.
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            Conditional weighted residuals (CWRES): a model diagnostic for the FOCE method.

            Population model analyses have shifted from using the first order (FO) to the first-order with conditional estimation (FOCE) approximation to the true model. However, the weighted residuals (WRES), a common diagnostic tool used to test for model misspecification, are calculated using the FO approximation. Utilizing WRES with the FOCE method may lead to misguided model development/evaluation. We present a new diagnostic tool, the conditional weighted residuals (CWRES), which are calculated based on the FOCE approximation. CWRES are calculated as the FOCE approximated difference between an individual's data and the model prediction of that data divided by the root of the covariance of the data given the model. Using real and simulated data the CWRES distributions behave as theoretically expected under the correct model. In contrast, in certain circumstances, the WRES have distributions that greatly deviate from the expected, falsely indicating model misspecification. CWRES/WRES comparisons can also indicate if the FOCE estimation method will improve the results of an FO model fit to data. Utilization of CWRES could improve model development and evaluation and give a more accurate picture of if and when a model is misspecified when using the FO or FOCE methods.
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              Retinoic acid and arsenic trioxide for acute promyelocytic leukemia.

              All-trans retinoic acid (ATRA) with chemotherapy is the standard of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%. Pilot studies of treatment with arsenic trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity. We conducted a phase 3, multicenter trial comparing ATRA plus chemotherapy with ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (white-cell count, ≤10×10(9) per liter). Patients were randomly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA. The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival at 2 years in the two groups was not greater than 5%. Complete remission was achieved in all 77 patients in the ATRA-arsenic trioxide group who could be evaluated (100%) and in 75 of 79 patients in the ATRA-chemotherapy group (95%) (P=0.12). The median follow-up was 34.4 months. Two-year event-free survival rates were 97% in the ATRA-arsenic trioxide group and 86% in the ATRA-chemotherapy group (95% confidence interval for the difference, 2 to 22 percentage points; P<0.001 for noninferiority and P=0.02 for superiority of ATRA-arsenic trioxide). Overall survival was also better with ATRA-arsenic trioxide (P=0.02). As compared with ATRA-chemotherapy, ATRA-arsenic trioxide was associated with less hematologic toxicity and fewer infections but with more hepatic toxicity. ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL. (Funded by Associazione Italiana contro le Leucemie and others; ClinicalTrials.gov number, NCT00482833.).

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                21 April 2021
                : 15
                : 1633-1640
                [1 ]Department of Pediatric, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College , Tianjin, People’s Republic of China
                [2 ]Department of Clinical Pharmacy, Clinical Trial Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital , Jinan, People’s Republic of China
                [3 ]Pediatric Hematology & Oncology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine , Shanghai, People’s Republic of China
                [4 ]Tianjin Institute of Pharmaceutical Research (TIPR) , Tianjin, People’s Republic of China
                [5 ]Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University , Jinan, People’s Republic of China
                Author notes
                Correspondence: Xiao-Fan Zhu Department of Pediatric, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College , 288 Nanjing Road, Tianjin, 300020, People’s Republic of ChinaTel/Fax +86 22 2390 9001 Email xfzhu@ihcams.ac.cn
                Wei Zhao Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University , No. 44, Wenhua West Road, Jinan, Shandong Province, People’s Republic of ChinaTel/Fax +86 531 8838 3308 Email zhao4wei2@hotmail.com

                These authors contributed equally to this work

                © 2021 Zhang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 1, Tables: 5, References: 23, Pages: 8
                Funded by: National Natural Science Foundation of China, open-funder-registry 10.13039/501100001809;
                Funded by: National Science and Technology;
                Funded by: Tianjin Municipal Science and Technology Commission;
                This work was supported in China by the National Natural Science Foundation of China (81870131), National Science and Technology Major Project (2017ZX09304024, 2017ZX09304029-002), Young Taishan Scholars Program of Shandong Province and Tianjin Municipal Science and Technology Commission Grant (15ZXLCSY00010).
                Original Research


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