Tianwu Yang1, Maria Thastrup2, Tania Nicole Masmas2, Hilde Hylland Uhlving2, Malene Johanne Petersen2, Anna Sofie Buhl Rasmussen2, Kjeld Schmiegelow2,3, Trine Meldgaard Lund1
1Department of Drug Design and Pharmacology, University of Copenhagen, Denmark, 2Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Denmark, 3Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark
Introduction: Busulfan is a chemotherapeutic drug that is widely used for conditioning regimens before hematopoietic stem cell transplantation (HSCT) for patients with malignant diseases (e.g., acute myeloid leukemia, myelodysplastic syndrome) (1). However, the pharmacokinetic profile of busulfan varies significantly, especially within the pediatric population (2). Higher exposure to busulfan can lead to dose-related side effects, including veno-occlusive disease and other severe toxicities with an increased risk of transplant-related mortality (3). On the other hand, low exposure will increase the probability of graft rejection or disease relapse (3). Thus, therapeutic drug monitoring (TDM) is recommended to ensure the individual patient achieves appropriate drug exposure. Currently, the target used in our center is a total AUC over the 4 days treatment with busulfan within 75-90mg*h/L for patients with malignant disease, depending on the diagnosis and the combination of other drugs given (3). Objective: This study aims to develop a new population pharmacokinetic model for adjusting doses on a daily basis. The model will include potential covariates that may affect the pharmacokinetic profile of busulfan in the pediatric population. Method: The population pharmacokinetic approach was performed on a retrospective dataset (2014-2024) of patients from the Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Demark. In total, 69 patients (2 adults and 67 children) with 649 observations were included. The patients received a 3h continuous infusion of busulfan over four consecutive days (dosing interval: 24h). Blood samples were taken for each patient at 0h, 0.5h, 1h, 2h, 4h, and 6h after the end of infusion. The M5 method was used to treat below limit of quantification data (BLOQ), which accounted for 5.2% of the total number of observations. NONMEM 7.5.0 was used for model development, and PsN 5.3.0 for the Visual Prediction Check (VPC) plot and Bootstrap. The covariate model was developed through the Stepwise Covariate Modeling (SCM) with forward selection (p<0.05) and backward elimination (p<0.001). The 95% confidence intervals (CI) for parameters were calculated by Bootstrap (samples = 2000). Results: A one-compartment model with inter-individual variability (IIV) on clearance (CL) and volume of distribution (V) and a combined additive and proportional residual unexplained error model was adequate to describe the data. The population CL and V for a typical pediatric patient with a weight of 23.8kg on the first day infusion was 5.67 L/h (95% CI [5.30, 6.12]) and 18.2 L (95% CI [17.07, 19.47]), respectively. The IIV of CL (?_CL²) and V (?_V²) were 0.117 (95% CI [0.06, 0.17]) and 0.0937 (95% CI [0.03, 0.16]), respectively. The total body weight and number of infusions were found to be significant covariates for both CL and V and only CL, respectively. Taking the CL on day 1 as reference, the CL of a typical patient would be decreased by an average of 10.4% and 13.2% on day 2 and day 3, respectively. Conclusion: A new population pharmacokinetic model for pediatric patients was developed and can potentially be useful for dose adjustments of pediatric patients before HSCT. A time-varying CL pattern was found, where the CL on days 2 and 3 was lower than that on day 1. This finding is consistent with previous research in other populations (4). The upcoming plan is to further validate the model through external data and build an easy-to-use, open-source app for daily TDM practice.
1. Neroutsos E, Nalda-Molina R, Paisiou A, Zisaki K, Goussetis E, Spyridonidis A, et al. Development of a Population Pharmacokinetic Model of Busulfan in Children and Evaluation of Different Sampling Schedules for Precision Dosing. Pharmaceutics [Internet]. 2022 Mar 15;14(3):647. Available from: http://www.ncbi.nlm.nih.gov/pubmed/35336021 2. Lawson R, Paterson L, Fraser CJ, Hennig S. Evaluation of two software using Bayesian methods for monitoring exposure and dosing once-daily intravenous busulfan in paediatric patients receiving haematopoietic stem cell transplantation. Cancer Chemother Pharmacol [Internet]. 2021 Sep 22;88(3):379–91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/34021809 3. Bartelink IH, Lalmohamed A, van Reij EML, Dvorak CC, Savic RM, Zwaveling J, et al. Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis. Lancet Haematol [Internet]. 2016 Nov 1;3(11):e526–36. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27746112 4. Takahashi T, Jaber MM, Brown SJ, Al-Kofahi M. Population Pharmacokinetic Model of Intravenous Busulfan in Hematopoietic Cell Transplantation: Systematic Review and Comparative Simulations. Clin Pharmacokinet [Internet]. 2023 Jul 6;62(7):955–68. Available from: http://www.ncbi.nlm.nih.gov/pubmed/37415003
Reference: PAGE 33 (2025) Abstr 11759 [www.page-meeting.org/?abstract=11759]
Poster: Drug/Disease Modelling - Oncology