{"doi":"10.1016/j.ejps.2023.106669","title":"Population pharmacokinetics of methotrexate and 7-hydroxymethotrexate and delayed excretion in infants and young children with brain tumors","abstract":"PURPOSE: The objectives of this study were to develop a population pharmacokinetic model of methotrexate (MTX) and its primary metabolite 7-hydroxymethotrexate (7OHMTX) in children with brain tumors, to identify the sources of pharmacokinetic variability, and to assess whether MTX and 7OHMTX systemic exposures were related to toxicity. METHODS: MTX as a 24-hour infusion and serial samples were analyzed for MTX and 7OHMTX by an LC-MS/MS method. Pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. Demographics, laboratory values, and genetic polymorphisms were considered as potential covariates to explain the pharmacokinetic variability. Association between MTX and 7OHMTX systemic exposures and MTX-related toxicities were explored using random intercept logistic regression models. RESULTS: , respectively. Baseline body surface area and estimated glomerular filtration rate were significant covariates on both MTX and 7OHMTX plasma disposition. Pharmacogenetic genotypes were associated with MTX pharmacokinetic parameters but had only modest influence. No significant association was observed between MTX or 7OHMTX exposure and MTX-related toxicity. CONCLUSIONS: MTX and 7OHMTX plasma disposition were characterized for the first time in young children with brain tumors. No exposure-toxicity relationship was identified in this study, presumably due to aggressive clinical management which led to a low MTX-related toxicity rate.","journal":"European Journal of Pharmaceutical Sciences","year":2023,"id":363238,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9277,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":579396,"name":"Jie Huang","orcid":"0000-0002-2466-2469","position":1,"is_corresponding":false},{"id":614298,"name":"Tong Lin","orcid":"0009-0009-3132-2356","position":2,"is_corresponding":false},{"id":662088,"name":"Wilburn E. Reddick","orcid":"0000-0002-1054-1201","position":3,"is_corresponding":false},{"id":1117718,"name":"Nicholas S. Selvo","orcid":null,"position":4,"is_corresponding":false},{"id":288898,"name":"Arzu Onar‐Thomas","orcid":"0000-0003-1005-2413","position":5,"is_corresponding":false},{"id":796063,"name":"Deborah Ward","orcid":"0000-0002-3603-964X","position":6,"is_corresponding":false},{"id":5549,"name":"Giles Robinson","orcid":"0000-0001-7441-9486","position":7,"is_corresponding":false},{"id":5546,"name":"Amar Gajjar","orcid":"0000-0001-5019-0699","position":8,"is_corresponding":false},{"id":558760,"name":"Clinton F. Stewart","orcid":"0000-0002-1546-9720","position":9,"is_corresponding":false},{"id":558757,"name":"Olivia Campagne","orcid":"0000-0001-6348-8910","position":0,"is_corresponding":true}],"reference_count":28,"raw_metadata":null,"created_at":"2026-07-19T01:14:28.054440Z","pmid":"38070781","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}