European journal of drug metabolism and pharmacokinetics · 2026
Population Pharmacokinetics of Melphalan in Pediatric Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation with Various Conditioning Regimens.
Клиническое исследование I фазыСтатьяНазвание и аннотация: Перевод в очереди
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Choi Jung Yoon, Kim Byungwook, Park Hyun Jin, Kim Bo Kyung, Hong Kyung Taek, Lee Soyoung, Lee SeungHwan, Kang Hyoung Jin
Аннотация
BACKGROUND AND OBJECTIVE: Melphalan 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.
METHODS: In 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.
RESULTS: Participant 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.
CONCLUSIONS: We 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).
METHODS: In 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.
RESULTS: Participant 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.
CONCLUSIONS: We 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).