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The pharmacokinetics (PKs) of methadone is highly variable due to the variability in alpha\u20101 acid glycoprotein (AAG) and genotypic differences in drug\u2010metabolizing enzymes. Additionally, the R and S enantiomers of methadone have unique PK and pharmacodynamic properties. This study aims to describe the PKs of R and S methadone and its metabolite 2\u2010ethylidene\u20101,5\u2010dimethyl\u20103,3\u2010diphenylpyrrolidine (EDDP) in pediatric surgical patients and to identify sources of inter\u2010 and intra\u2010individual variability. Children aged 8\u201317.9\u00a0years undergoing orthopedic surgeries received intravenous methadone 0.1\u00a0mg\/kg intra\u2010operatively followed by oral methadone 0.1\u00a0mg\/kg postoperatively every 12\u00a0h. Pharmacokinetics of R and S methadone and EDDP were determined using liquid chromatography tandem mass spectrometry assays and the data were modeled using nonlinear mixed\u2010effects modeling in NONMEM. R and S methadone PKs were well\u2010described by two\u2010compartment disposition models with first\u2010order absorption and elimination. EDDP metabolites were described by one compartment disposition models with first order elimination. Clearance of both R and S methadone were allometrically scaled by bodyweight. CYP2B6 phenotype was a determinant of the clearance of both the enantiomers in an additive gene model. The intronic CYP3A4 single\u2010nucleotide polymorphism (SNP) rs2246709 was associated with decreased clearance of R and S methadone. Concentrations of AAG and the SNP of AAG rs17650 independently increased the volume of distribution of both the enantiomers. The knowledge of these important covariates will aid in the optimal dosing of methadone in children.<\/jats:p>","DOI":"10.1002\/psp4.12687","type":"journal-article","created":{"date-parts":[[2021,8,26]],"date-time":"2021-08-26T10:41:53Z","timestamp":1629974513000},"page":"1183-1194","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Pharmacokinetic modeling of R and S\u2010Methadone and their metabolites to study the effects of various covariates in post\u2010operative children"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2082-6454","authenticated-orcid":false,"given":"Blessed W.","family":"Aruldhas","sequence":"first","affiliation":[{"name":"Department of Anesthesia Indiana University School of Medicine Indianapolis Indiana USA"},{"name":"Division of Clinical Pharmacology Department of Medicine Indiana University School of Medicine Indianapolis Indiana 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