Prediction of Busulfan Clearance by Predose Plasma Metabolomic Profiling

Abstract

Intravenous busulfan doses are often personalized to a target plasma exposure (targeted busulfan) using an individual's busulfan clearance (BuCL). We evaluated whether BuCL could be predicted by a predose plasma panel of 841 endogenous metabolomic compounds (EMCs). In this prospective cohort of 132 hematopoietic cell transplantation (HCT) patients, all had samples collected immediately before busulfan administration (preBU) and 96 had samples collected 2 weeks before busulfan (2-week-preBU). BuCL was significantly associated with 37 EMCs after univariate linear regression analysis and controlling for false discovery (< 0.05) in the 132 preBU samples. In parallel, with preBU samples, we included all 841 EMCs in a least absolute shrinkage and selection operator-penalized regression which selected 13 EMCs as predominantly associated with BuCL. Then, we constructed a prediction model by estimating coefficients for these 13 EMCs, along with sex, using ordinary least-squares. When the resulting linear prediction model was applied to the 2-week-preBU samples, it explained 40% of the variation in BuCL (adjusted R² = 0.40). Pathway enrichment analysis revealed 18 pathways associated with BuCL. Lysine degradation followed by steroid biosynthesis, which aligned with the univariate analysis, were the top two pathways. BuCL can be predicted before busulfan administration with a linear regression model of 13 EMCs. This pharmacometabolomics method should be prioritized over use of a busulfan test dose or pharmacogenomics to guide busulfan dosing. These results highlight the potential of pharmacometabolomics as a precision medicine tool to improve or replace pharmacokinetics to personalize busulfan doses.

Figure 1

Accurate prediction of by the model of the EMCs in the 2‐week pre‐busulfan sample. Busulfan clearance is calculated using maximum a posteriori probability Bayesian estimation and reported in the units of mL/min/kg of normal fat mass. Panel (a) shows the predicted (x‐axis) and the actual (y‐axis) busulfan clearance model. The predicted clearance has a higher predictive power among patients with lower clearance. Panel (b) shows a box plot of the ratio between the predicted and actual clearance. Middle line is the median; top and bottom of the box show 25^th and 75^th percentile (i.e., the interquartile range or IQR); top whisker shows the 1.5×IQR above the 75% upper box, and bottom whisker means the minimum since it is within the 1.5×IQR below the 25% bottom box.

Figure 2

Working hypothesis for the pathways associated with busulfan clearance. Our working hypothesis is that glutathione metabolism (yellow box) continues to be central to busulfan clearance. We confirmed our prior findings of the association of the glycine, serine, and threonine pathway (red box) and bile acids (green box) with busulfan clearance. The impact of mitochondrial dysfunction (blue box) and reactive oxygen species was also found. CAR, constitutive androstane receptor; GST, glutathione transferase.