Razan Sakran1,2, Xiaomei Chen2, Daniel Kurnik1,3, Elisabet Nielsen2
1Clinical Pharmacology Unit, Rambam Health Care Campus, Israel, 2Department of Pharmacy, Clinical Pharmacy, Uppsala University, Uppsala, Sweden, 3Rappaport Faculty of Medicine, Technion – Israel Institute of Technology
Personalizing Busulfan Exposure in Hematopoietic Cell Transplantation Razan Sakran (1,2), Xiaomei Chen (2), Daniel Kurnik (1,3), Elisabet I Nielsen (2) (1)Clinical Pharmacology Unit, Rambam Health Care Campus, Israel, (2) Department of Pharmacy, Clinical Pharmacy, Uppsala University, Uppsala, Sweden, (3) Rappaport Faculty of Medicine, Technion – Israel Institute of Technology Introduction: Busulfan is an alkylating agent widely used in conditioning regimens before hematopoietic stem cell transplantation (HCT). Busulfan has a narrow therapeutic window, large inter-individual variability (IIV), and a well-established pharmacokinetic (PK)–pharmacodynamic (PD) relationship, and model-informed precision dosing is thus recommended to achieve target exposure (1). Various population PK (PopPK) models have been proposed to address busulfan dosing (2,3), but most models were developed based on specific patient subgroups (adults or children) receiving the drug intravenously. Moreover, these models do not account for infusion lag time caused by the dead space of the infusion tube. Objectives: 1.To develop a PopPK model for oral and IV busulfan dosing in HCT patients of all ages 2.To explore the effect of infusion lag time on model performance Methods: We retrospectively collected data from pediatric and adult HCT patients who had received IV or oral busulfan, and underwent extensive blood sampling (9-10 time points) with plasma concentrations measured at the Clinical Pharmacology and Toxicology Department of the Rambam Health Care Campus. We used the NONMEM software to build a popPK model exploring different absorption and elimination structures and the effect of covariates, including body size descriptors (weight, height, BSA, normal fat mass), age, and sex, on PK parameters using stepwise covariate modelling. We also examined the effect of infusion lag time (estimated empirically or mechanistically) on the objective function (OFV), residual unexplained variability (RUV), and goodness of fit plots. Results: We used data from 253 pediatric (median age, 4.7 years; interquartile range (IQR), 2.0 to 9.3 years) and 274 adult HCT patients (median age, 52 years; IQR, 38-61 years). All children received IV busulfan, while among adults, 217 (79.1%) received oral busulfan. The PopPK model for oral and IV busulfan was best described using a two-compartment disposition model with linear elimination and first-order absorption. The effect of body weight on PK parameters was described using a power model with fixed allometric exponents, and the effect of age on clearance (CL) using a maturation sigmoidal function. For a 70-kg patient, the CL was 11.2 L/h [3%] (typical value [relative standard error]), the inter-compartmental clearance (Q) was 1.71 L/h [13%], the volume of the central compartment (Vc) was 49.1 L [2%], and the volume of the peripheral compartment (Vp) was 211 L [14%]. The oral bioavailability was 0.95 [2%]. The IIV in CL, Vc, and Q, expressed as coefficients of variation (CV%), were 26.1%, 22.0%, and 66.9%. The inter-occasion variability for the absorption rate constant (ka) was high (CV=97.8%), but low for CL (CV=9.7%). Inclusion of infusion lag time significantly decreased OFV, improved diagnostic plots, and decreased RUV. RUV was best described using a combined, time-dependent error model (5). Combining oral and IV data allowed the characterization of the distribution and elimination phases, which was not possible with oral data alone. Conclusion: We developed a comprehensive PopPK model for oral and IV busulfan in patients with a wide age spectrum. We plan to implement this model in daily clinical practice.
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Reference: PAGE 33 (2025) Abstr 11657 [www.page-meeting.org/?abstract=11657]
Poster: Drug/Disease Modelling - Oncology