Population Pharmacokinetics of Melphalan in Pediatric Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation with Various Conditioning Regimens

초록

Background and ObjectiveMelphalan is an alkylating agent used in conditioning regimens for hematopoietic stem cell transplantation (HSCT) in pediatric patients. In this study, we aimed to develop a population pharmacokinetic (PK) model of melphalan in pediatric patients undergoing various conditioning regimens.MethodsIn total, 20 pediatric patients who received one or two consecutive doses of melphalan were included in this study. PK data were analyzed using a nonlinear mixed-effects model. Evaluated covariates included body weight (WT), sex, estimated glomerular filtration rate (eGFR), creatinine, hematocrit, prior radiation therapy, concomitant drugs (conditioning regimen), and blood albumin levels. Systemic melphalan exposure was simulated using covariates included in the final model.ResultsParticipant ages ranged from 0.6 to 17.4 years. Melphalan PK was best described by a two-compartment model with proportional residual error. Significant covariates were concomitant busulfan and creatinine on clearance, and WT on clearance and the central and peripheral volumes of distribution. Final parameter estimates (normalized to a WT of 28 kg) were as follows: clearance, 24.9 L/h; central compartment volume, 13.4 L; intercompartmental clearance, 14.5 L/h; and peripheral compartment volume, 7.37 L. Simulations indicated that concomitant busulfan was associated with an approximately 1.17 to 1.19-fold increase in melphalan exposure, while patients with lower WT (7.9 kg) showed an approximately 1.12 to 1.13-fold higher exposure than those with high WT (66.7 kg) within the same regimen group.ConclusionsWe developed a preliminary PK model for melphalan in pediatric patients with varying WT levels, conditioning regimens, and renal functions. Our findings suggest that concomitant busulfan contribute to variability in melphalan exposure, indicating its potential application in personalized therapy.(NCT04937634)ConclusionsWe developed a preliminary PK model for melphalan in pediatric patients with varying WT levels, conditioning regimens, and renal functions. Our findings suggest that concomitant busulfan contribute to variability in melphalan exposure, indicating its potential application in personalized therapy.(NCT04937634)

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