Presentation Title: Population pharmacokinetics of R and S methadone in children undergoing major surgery
Author Name(s): Blessed W. Aruldhas1,3, Brian R. Overholser1,2, Sara K. Quinney1, Andrea R. Masters1, Christine M. Bach1, Senthil Sadhasivam1
Author Department and School Affiliation: 1Indiana University School of Medicine, Indianapolis, IN; 2Purdue University College of Pharmacy, Indianapolis, IN; 3Christian Medical College, Vellore, India
Methadone is a racemic synthetic opioid used for postoperative analgesia in addition to its widespread use in opioid abuse disorder. The individual enantiomers vary in their pharmacokinetic and pharmacodynamic properties. The optimal dose required to achieve therapeutic concentrations for effective analgesia in children is not fully known.
Methadone was given to 38 children both intravenously in the operating room and orally at a dose of 0.05 to 0.1 mg/kg every 12 hours. Blood samples were collected on multiple occasions over 3 to 5 inter-dose intervals. R-methadone, S-methadone and AAG (acid alpha glycoprotein) concentrations were measured using liquid chromatography. The pharmacokinetic data were analyzed using a nonlinear mixed effect modeling approach in NONMEM(v7.4) using FOCE method with interactions.
The pharmacokinetics of both R and S-methadone were described by two-compartment disposition models with linear elimination and first order absorption. AAG (alpha-acid-glycoprotein) was identified as a covariate on central volume for both the enantiomers (Δ OFV = 11.5 and 12.4 respectively). Visual predictive checks and bootstrapping validated the present model.
Pharmacokinetic models were successfully created for both R and S methadone in children. AAG and BMI were important covariates describing the volume of central compartment in children.