Metabolon Elucidates Novel Biomarkers to Improve Busulfan Dosing Strategies

The Challenge: Improving Busulfan Dosing Strategies

Busulfan is a chemotherapy drug used to treat certain types of cancer, including chronic myeloid leukemia (CLM) and some types of non-Hodgkin’s lymphoma. Many patients also receive high-dose busulfan as part of a conditioning regimen before a bone marrow transplant.  Busulfan works by killing fast-growing cells, but also affects normal cells that divide quickly—this can lead to side effects such as low blood counts, nausea, and diarrhea. Pharmacokinetic (PK)-guided busulfan dosing strategies aim to achieve a target therapeutic level of the drug in the patient’s bloodstream while minimizing toxicity. Although PK-guided busulfan dosing is considered an effective way to ensure optimal busulfan efficacy, this process is resource-intensive, labor-intensive, and time-sensitive. Thus, alternative approaches are needed to determine the appropriate busulfan dose for each patient. Metabolomics could improve or ideally replace PK-guided busulfan dosing to achieve the desired therapeutic effect while minimizing the risk of toxicity.

Metabolon Insight: Metabolomics Can Elucidate Biomarkers Associated with Busulfan Clearance

This study utilized the Metabolon Global Discovery Panel to profile the plasma of patients two weeks before (n = 96) and immediately before (n = 132) busulfan administration.¹ The panel’s unrivaled coverage of up to 5,400 semi-quantifiable metabolites offered this group the most comprehensive solution to elucidate endogenous metabolomic compounds (EMCs) or biomarkers associated with busulfan clearance from plasma.

The Solution: Metabolon Helped Identify 13 Biomarkers Associated with Busulfan Clearance

Metabolomics analysis revealed the presence of 841 EMCs in the plasma samples of patients before busulfan administration. The research group then evaluated whether the presence of certain EMCs could predict intravenous busulfan clearance. Statistical analysis of the plasma samples obtained immediately before busulfan administration identified 13 EMCs as predominantly associated with busulfan clearance. These EMCs included urate, mannonate, lysine, cortisone, and cortisol. These 13 EMCs were later used to create a linear prediction model that was shown to have strong predictive power. When this model was applied to the two-week-pre-busulfan samples, the predicted vs. actual busulfan clearance values were strongly correlated (R² = 0.40). This model had the highest predictive power among patients with lower clearance (R² = 0.53). Pathway enrichment analysis of all the EMCs showed that lysine degradation was the most significant pathway in both sample groups.

The Outcome: Metabolon Can Help Optimize Busulfan Dosing

The Global Discovery Panel helped this research group develop a more efficient method of estimating busulfan clearance. Metabolon found that by analyzing plasma obtained two weeks before administering busulfan, 13 endogenous metabolomic compounds could accurately predict the clearance of intravenous busulfan, particularly in patients with slow clearance. These results demonstrate that metabolomics can guide busulfan dosage to ensure that each patient receives the appropriate drug dosage. The study shows that metabolomics can be leveraged to identify new biomarkers, which can help optimize drug dosing.