High dose busulphan (Bu) is an essential component of myeloablative regimens prior to Haematopoietic Stem Cell Transplantation (HSCT), but is subject to significant inter- and intra-individual pharmacokinetic variability, which is a challenge for accurate dosing within the therapeutic window. Furthermore, sinusoidal obstruction syndrome (SOS) remains a major toxicity of Bu overexposure despite the addition of prophylaxis to the chemotherapy regimen.
We investigated the factors behind the pharmacokinetic variability of Bu and its relationship with SOS. Pharmacokinetic and transplant-relevant data were collected on 138 episodes of myeloablative conditionings in 133 patients who received a haematopoietic stem cell transplant at the Children’s Hospital at Westmead between 2006-2017. A population pharmacokinetic approach was used to develop a model to determine the AUC for each dose. The cumulative AUC was calculated as the sum of all the AUCs for Bu doses in one myeloablative conditioning episode. The association between SOS and cumulative AUC was then assessed using an unpaired T-test.
Non-linear mixed effects modelling was performed on NONMEM version 7.3 through the Pirana workbench with FOCE-I. A one-compartment model with a proportional error model best described the 1,890 observations. Intra-occasion variability on CL and V further improved the model (dOFV 741). Weight with allometric scaling was incorporated as a covariate into the model to account for the large variability in body size of the patients. Further exploration of covariates through genotype and concomitant medications is ongoing. Clearance (3.75 L/h) and volume (11 L) were consistent with literature values. Cumulative AUC of Bu was highly variable (29.41-130.39 mg·h/L), with a large portion of patients falling out of target ranges. However, there was no distinction in the cumulative AUC for patients with or without SOS. Based on these findings, variation in Bu AUC alone does not explain the incidence of SOS.