Population Pharmacokinetics of Melphalan for Pediatric Patients Undergoing Hematopoietic Cell Transplantation

Melphalan is an alkylating agent used as part of conditioning prior to pediatric hematopoietic cell transplantation (HCT). We performed a single-center, prospective pharmacokinetic study of 37 pediatric patients undergoing HCT from March 2015 to 2019. The primary objective was to develop and validate a population pharmacokinetic model for melphalan in a diverse group of pediatric HCT recipients. Nonlinear mixed-effects modeling was implemented to describe plasma concentration-time data of melphalan. A 2-compartment, proportional error model with weight on clearance best fit the data. Final parameter estimates were clearance, 19.1 L/h/25 kg; volume of the central compartment, 8.5 L/25 kg; volume of the peripheral compartment, 5.8 L/25 kg; and intercompartmental clearance 12.4 L/h/25 kg. Residual unexplained variability was low, at 12.5%. Results suggest the empiric weight-based dosing (mg/kg) used in children <12 kg or 2 years of age may result in subtherapeutic exposure. Model-based dosing of melphalan in pediatric HCT may help inform individualized dosing strategies to improve clinical outcomes and limit drug-related adverse events in pediatric HCT recipients.