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Aims: Azathioprine (AZA) and 6-mercaptopurine are prescribed in acute lymphoblastic leukaemia (ALL) and inflammatory bowel diseases (IBD). Metabolism to active 6-thioguanine (6TGN) and 6-methylmercaptopurine nucleotides (6MMPN) is variable but therapeutic drug monitoring (TDM) remains debatable. This study reports on factors impacting on red blood cell (RBC) metabolites concentrations in children to facilitate TDM interpretation., Methods: The first paediatric TDM samples received during year 2021 were analysed, whatever indication and thiopurine drug. Target concentration ranges were 200-500, <6000 pmol/8 × 10 8 RBC for 6TGN and 6MMPN., Results: Children (n = 492) had IBD (64.8%), ALL (22.6%) or another autoimmune disease (12.6%): mean ages at TDM were 7.5 in ALL and 13.7 years in IBD (P < .0001). ALL received 6-mercaptopurine (mean dose 1.7 mg/kg/d with methotrexate), IBD received AZA (1.9 mg/kg/d with anti-inflammatory drugs and/or monoclonal antibodies). Median 6TGN and 6MMPN concentrations were 213.7 [interquartile range: 142.5; 309.6] and 1144.6 [419.4; 3574.3] pmol/8 × 10 8 RBC, 38.8% of patients were in the recommended therapeutic range for both compounds. Aminotransferases and blood tests were abnormal in 57/260 patients: 8.1% patients had high alanine aminotransaminase, 3.4% of patients had abnormal blood count. Factors associated with increased 6TGN were age at TDM and thiopurine methyltransferase genotype in ALL and AZA dose in IBD. The impact of associated treatment in IBD patients was also significant., Conclusion: TDM allowed identification of children who do not reach target levels or remain over treated. Including TDM in follow-up may help physicians to adjust dosage with the aim of reducing adverse effects and improve treatment outcome., (© 2023 British Pharmacological Society.)

Maintenance therapy is the last phase of treatment for acute lymphoblastic leukemia in children and adolescents. Although maintenance therapy is associated with toxicities and specific management issues, it is an essential phase of treatment that reduces the risk of relapse. The objective of this work is to propose a guide for the initiation, administration, and monitoring of maintenance therapy, and for the management of food, schooling, leisure, community life, risk of infection and links with family medicine., (Copyright © 2022 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

We evaluated the population pharmacokinetics of caspofungin in children (2 to 12 years of age). The real-world data from 48 children were best fit by a two-compartment model with first-order elimination. Subsequent covariate analysis demonstrated that body surface area had a significant correlation with caspofungin pharmacokinetics, compared to body weight. The population pharmacokinetics of caspofungin confirmed that adjustment of caspofungin dosage based on body surface area is most appropriate for pediatric use., (Copyright © 2019 American Society for Microbiology.)

Methotrexate (MTX) is a key agent for the treatment of acute lymphoblastic leukemia in children and the benefit of high-dose MTX is well established as it significantly increases cure rates and improves patients' prognosis. However, the determinants of MTX therapeutic effect are not clearly identified, although intracellular polyglutamation is essential. MTX, the monoglutamate form (MTXG₁) inhibits the dihydrofolate reductase (DHFR) implicated in the folate cycle. MTXG₁ is metabolized to active methotrexate polyglutamates (MTXPG) with sequential gamma-linkage of 2 to 6 glutamyl residues by the folylpolyglutamate synthetase (FPGS). Long chain MTXPG have higher affinity than MTX for the enzymes involved in de novo purine synthesis such as 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC) and thymidilate synthase (TS), which results in a reinforcement of MTX inhibition. Thus, intracellular formation of MTXPG enhances the cytotoxic and antileukemic effect of MTX. Different pharmacogenetic polymorphisms contribute to interindividual variability in MTX response to treatment. In addition, pharmacokinetic interactions with 6-mercaptopurine (6-MP), frequently co-administered, have been reported. And factors affecting intracellular MTX disposition and 6-MP/MTX interactions, including pharmacogenetic polymorphisms affecting MTX disposition are reviewed.