Population pharmacokinetics of Busulfan and its metabolite sulfolane in patients with myelofibrosis undergoing hematopoietic stem cell transplantation

For patients with myelofibrosis, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative treatment to date. Busulfan-based conditioning regimens are commonly used, although high inter-individual variability (IIV) in busulfan drug exposure makes individual dose selection challenging. Since data regarding the IIV in patients with myelofibrosis are sparse, this study aimed to develop a population pharmacokinetic (PopPK) model of busulfan and its metabolite sulfolane in patients with myelofibrosis. The influence of patient-specific covariates on the pharmacokinetics of drug and metabolite was assessed using non-linear mixed effects modeling in NONMEM (R). We obtained 523 plasma concentrations of busulfan and its metabolite sulfolane from 37 patients with myelofibrosis. The final model showed a population clearance (CL) and volume of distribution (V-d) of 0.217 L/h/kg and 0.82 L/kg for busulfan and 0.021 L/h/kg and 0.65 L/kg for its metabolite. Total body weight (TBW) and a single-nucleotide polymorphism of glutathione-S-transferase A1 (GSTA1 SNP) displayed a significant impact on volume of distribution and metabolite clearance, respectively. This is the first PopPK-model developed to describe busulfan's pharmacokinetics in patients with myelofibrosis. Incorporating its metabolite sulfolane into the model not only allowed the characterization of the covariate relationship between GSTA1 and the clearance of the metabolite but also improved the understanding of busulfan's metabolic pathway.