Pharmacometabonomic Prediction of Busulfan Clearance in Hematopoietic Cell Transplant Recipients

Navarro, Sandi L.; Randolph, Timothy W.; Shireman, Laura M.; Raftery, Daniel; McCune, Jeannine S.

doi:10.1021/acs.jproteome.6b00370

Cited by 23 publications

(29 citation statements)

References 58 publications

(120 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To generate an a priori hypothesis regarding metabolomic pathways associated with the ratio of 4HCY/CY AUC, we analyzed an existing dataset with 4HCY/CY AUC 14 and EMCs 15 available. This hypothesis‐generation dataset was obtained from a separate cohort of 51 HCT recipients conditioned with CY (60 mg/kg/day i.v.…”

Section: Methodsmentioning

confidence: 99%

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

Nakamura

O’Meally

Randolph

et al. 2022

Clinical Translational Sci

Self Cite

View full text Add to dashboard Cite

The widely used alkylating agent cyclophosphamide (CY) has substantive interpatient variability in the area under the curve (AUC) of it and its metabolites.Numerous factors may influence the drug-metabolizing enzymes that metabolize CY to 4-hydroxycyclophosphamide (4HCY), the principal precursor to CY's cytotoxic metabolite. We sought to identify endogenous metabolomics compounds (EMCs) associated with 4HCY formation clearance (ratio of 4HCY/CY AUC) using global metabolomics. Patients who undergo hematopoietic cell transplantation receiving post-transplant CY (PT-CY) were enrolled, cohort 1 (n = 26) and cohort 2 (n = 25) donating longitudinal blood samples before they started HCT (pre-HCT), before infusion of the donor allograft (pre-graft), before the first dose of PT-CY (pre-CY), and 24 h after the first dose of PT-CY (24-h post-CY), which is also immediately before the second dose of CY. A total of 512 and 498 EMCs were quantitated in two cohorts, respectively. Both univariate linear regression with false discovery rate (FDR), and pathway enrichment analyses using a global association test were performed. At the pre-CY time point, no EMCs were associated at FDR less than 0.1. At pre-HCT, cohort 1 had one EMC (levoglucosan) survive the FDR threshold. At pre-graft, cohort 1 and cohort 2 had 20 and 13 EMCs, respectively, exhibiting unadjusted p values less than 0.05, with the only EMCs having an FDR less than 0.1 being two unknown EMCs. At 24-h post-CY, there were three EMCs, two ketones, and threitol, at FDR less than 0.1 in cohort 2. These results demonstrate the potential of pharmacometabonomics, but future studies in larger samples are needed to optimize CY. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?We report the first pharmacometabonomic study of the association of plasma EMCs with cyclophosphamide pharmacokinetics, specifically the ratio of 4HCY/ CY AUC.

show abstract

Section: Methodsmentioning

confidence: 99%

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

Nakamura

O’Meally

Randolph

et al. 2022

Clinical Translational Sci

Self Cite

View full text Add to dashboard Cite

show abstract

“…A pathways analysis of 80 Homo sapiens metabolic pathways was undertaken with the normalized data to determine if different metabolic pathways were perturbed between the Mn-unexposed and -exposed groups. Twenty-three pathways were identified that included at least four of the 224 metabolites, which is considered the minimum number for meaningful pathway analysis ( 36 , 37 ). Of these 23 pathways, seven had a FDR < 0.1, indicating a significant perturbation in the pathway between exposed and unexposed workers: beta-alanine metabolism, propanoate metabolism, pyrimidine metabolism, pantothenate and CoA biosynthesis, primary bile acid biosynthesis, histidine metabolism, and glycine, serine, and threonine metabolism.…”

Section: Resultsmentioning

confidence: 99%

Short Report: Using Targeted Urine Metabolomics to Distinguish Between Manganese Exposed and Unexposed Workers in a Small Occupational Cohort

Carter

Simpson

Raftery

et al. 2021

Front. Public Health

Self Cite

View full text Add to dashboard Cite

Objectives: Despite the widespread use of manganese (Mn) in industrial settings and its association with adverse neurological outcomes, a validated and reliable biomarker for Mn exposure is still elusive. Here, we utilize targeted metabolomics to investigate metabolic differences between Mn-exposed and -unexposed workers, which could inform a putative biomarker for Mn and lead to increased understanding of Mn toxicity.Methods: End of shift spot urine samples collected from Mn exposed (n = 17) and unexposed (n = 15) workers underwent a targeted assay of 362 metabolites using LC-MS/MS; 224 were quantified and retained for analysis. Differences in metabolite abundances between exposed and unexposed workers were tested with a Benjamini-Hochberg adjusted Wilcoxon Rank-Sum test. We explored perturbed pathways related to exposure using a pathway analysis.Results: Seven metabolites were significantly differentially abundant between exposed and unexposed workers (FDR ≤ 0.1), including n-isobutyrylglycine, cholic acid, anserine, beta-alanine, methionine, n-isovalerylglycine, and threonine. Three pathways were significantly perturbed in exposed workers and had an impact score >0.5: beta-alanine metabolism, histidine metabolism, and glycine, serine, and threonine metabolism.Conclusion: This is one of few studies utilizing targeted metabolomics to explore differences between Mn-exposed and -unexposed workers. Metabolite and pathway analysis showed amino acid metabolism was perturbed in these Mn-exposed workers. Amino acids have also been shown to be perturbed in other occupational cohorts exposed to Mn. Additional research is needed to characterize the biological importance of amino acids in the Mn exposure-disease continuum, and to determine how to appropriately utilize and interpret metabolomics data collected from occupational cohorts.

show abstract

“…Glycine levels, an important substrate in GSH synthesis, were positively associated with busulfan clearance. 35 In previous research N-acetylcysteine was found to potentially serve as prophylactic agent against sinusoidal obstructive syndrome induced by busulfan. 37,38 Also, evidence was provided that N-acetylcysteine does not interfere with the myeloablative effect of busulfan.…”

Section: Discussionmentioning

confidence: 99%

A semi‐mechanistic model based on glutathione depletion to describe intra‐individual reduction in busulfan clearance

Langenhorst

Boss

Kesteren

et al. 2020

Brit J Clinical Pharma

View full text Add to dashboard Cite

Aim:To develop a semi-mechanistic model, based on glutathione depletion and predict a previously identified intra-individual reduction in busulfan clearance to aid in more precise dosing. Methods:Busulfan concentration data, measured as part of regular care for allogeneic hematopoietic cell transplantation (HCT) patients, were used to develop a semimechanistic model and compare it to a previously developed empirical model. The latter included an empirically estimated time effect, where the semi-mechanistic model included theoretical glutathione depletion. As older age has been related to lower glutathione levels, this was tested as a covariate in the semi-mechanistic model. Lastly, a therapeutic drug monitoring (TDM) simulation was performed comparing the two models in target attainment. Results:In both models, a similar clearance decrease of 7% (range −82% to 44%), with a proportionality to busulfan metabolism, was found. After 40 years of age, the time effect increased with 4% per year of age (0.6-8%, P = 0.009), causing the effect to increase more than a 2-fold over the observed age-range (0-73 years). Compared to the empirical model, the final semi-mechanistic model increased target attainment from 74% to 76%, mainly through better predictions for adult patients. Conclusion:These results suggest that the time-dependent decrease in busulfan clearance may be related to gluthathione depletion. This effect increased with older age (>40 years) and was proportional to busulfan metabolism. The newly constructed semi-mechanistic model could be used to further improve TDM-guided exposure target attainment of busulfan in patients undergoing HCT. K E Y W O R D Schemotherapyoncology, drug safetyclinical pharmacology, pharmacokinetics, therapeutic drug monitoringclinical pharmacologyThe authors confirm that the Principal Investigator for this paper is Dr E. M. van Maarseveen and that he had direct clinical responsibility for patients.

show abstract

Pharmacometabonomic Prediction of Busulfan Clearance in Hematopoietic Cell Transplant Recipients

Cited by 23 publications

References 58 publications

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

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

Short Report: Using Targeted Urine Metabolomics to Distinguish Between Manganese Exposed and Unexposed Workers in a Small Occupational Cohort

A semi‐mechanistic model based on glutathione depletion to describe intra‐individual reduction in busulfan clearance

Contact Info

Product

Resources

About