Prediction of intravenous busulfan clearance by endogenous plasma biomarkers using global pharmacometabolomics

Abstract

Introduction High-dose busulfan (busulfan) is an integral part of the majority of hematopoietic cell transplantation conditioning regimens. Intravenous (IV) busulfan doses are personalized using pharmacokinetics (PK)-based dosing where the patient’s IV busulfan clearance is calculated after the first dose and is used to personalize subsequent doses to a target plasma exposure. PK-guided dosing has improved patient outcomes and is clinically accepted but highly resource intensive. Objective We sought to discover endogenous plasma biomarkers predictive of IV busulfan clearance using a global pharmacometabolomics-based approach. Methods Using LC-QTOF, we analyzed 59 (discovery) and 88 (validation) plasma samples obtained before IV busulfan administration. Results In the discovery dataset, we evaluated the association of the relative abundance of 1885 ions with IV busulfan clearance and found 21 ions that were associated with IV busulfan clearance tertiles (r2 ≥ 0.3). Identified compounds were deoxycholic acid and/or chenodeoxycholic acid, and linoleic acid. We used these 21 ions to develop a parsimonious seven-ion linear predictive model that accurately predicted IV busulfan clearance in 93% (discovery) and 78% (validation) of samples. Conclusion IV busulfan clearance was significantly correlated with the relative abundance of 21 ions, seven of which were included in a predictive model that accurately predicted IV busulfan clearance in the majority of the validation samples. These results reinforce the potential of pharmacometabolomics as a critical tool in personalized medicine, with the potential to improve the personalized dosing of drugs with a narrow therapeutic index such as busulfan.

Pharmacometabonomic association of cyclophosphamide 4‐hydroxylation in hematopoietic cell transplant recipients

“…These studies, as well as our own evaluating the association of the plasma EMCs with i.v. busulfan clearance, 15 , 33 highlights the opportunity pharmacometabonomics could offer to improve clinical outcomes. We chose to focus on the alkylating agent CY because of its increasing use of GVHD prophylaxis and preclinical data showing that moderate doses may be effective.…”

Metabolomics technology and bioinformatics for precision medicine

“…Several projects and databases are focused on defining human metabolome as well as species-centered or diseasecentered metabolomes, microbiome metabolome and exposome [27,28,[76][77][78][79][80][81][82][83]. [84][85][86], plasma [11,87], urine, cerebrospinal fluid, ascitic fluid [88], saliva [89][90][91], tear [92], bronchial wash (BW) and bronchoalveolar lavage fluid [93], seminal fluid [94], prostatic secretions [94] or fecal samples [95]. Tissue analysis is more complicated because of tissue heterogeneity and often limited sample volume.…”

“…As a global approach that can measure all or a large number of cellular metabolites, metabolomics is distinctively positioned to provide a unique metabolic readout of patient's physiological or disease state [3]. Mass spectrometry (MS)-based and nuclear magnetic resonance (NMR)-based approaches are now routinely used for newborn screening [4][5][6][7][8], drug screening [9,10], pharmacometabolomics [11][12][13][14][15][16][17][18], bacterial identification [19][20][21], metabolic imaging [22][23][24][25] or gut flora analysis [26][27][28][29].…”

Metabolomic and transcriptomic analysis reveals endogenous substrates and metabolic adaptation in rats lacking Abcg2 and Abcb1a transporters

“…Untargeted metabolomics has been previously used to identify endogenous drug transporter substrates (e.g., for OATP and OAT transporters) [14][15][16]. Understanding of the transporter's effect on the metabolome may also help interpret whether metabolomic signatures attributed to drug response, toxicities or side effects (pharmacometabolomics) [17,18], are revealing a drug's inhibition/competition with these transporters.…”