Pharmacogenomic associations of cyclophosphamide pharmacokinetic candidate genes with 4hydroxycyclophosphamide formation in children with Cancer.

Publisher: Springer Verlag Country of Publication: Germany NLM ID: 7806519 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0843 (Electronic) Linking ISSN: 03445704 NLM ISO Abbreviation: Cancer Chemother Pharmacol Subsets: MEDLINE

Publication: Berlin : Springer Verlag
Original Publication: Berlin, New York, Springer International.

Cyclophosphamide*/pharmacokinetics ; Cyclophosphamide*/administration & dosage ; Cyclophosphamide*/analogs & derivatives ; Neoplasms*/drug therapy ; Neoplasms*/genetics ; Polymorphism, Single Nucleotide* ; Pharmacogenetics*; Humans ; Child ; Female ; Male ; Child, Preschool ; Adolescent ; Infant ; Area Under Curve ; Age Factors

Purpose: 4-hydroxycyclophosphamide (4HCY) is the principal precursor to the cytotoxic metabolite of cyclophosphamide (CY), which is often used as first-line treatment of children with cancer. There is conflicting data regarding the relationship between CY efficacy, toxicity, and pharmacokinetics with the genes encoding proteins involved in 4HCY pharmacokinetics, specifically its formation and elimination.
Methods: We evaluated germline pharmacogenetics in children with various malignancies receiving their first CY dose. Using linear regression, we analyzed the associations between two pharmacokinetic outcomes - how fast a child cleared CY (i.e., CY clearance) and the ratio of the 4HCY/CY exposure, specifically area under the plasma concentration-time curve (AUC), and 372 single nucleotide polymorphisms (SNP) in 14 drug-metabolizing transporters or enzymes involved in 4HCY formation or elimination.
Results: Age was associated with the ratio of 4HCY/CY AUC (P = 0.004); Chemotherapy regimen was associated with CY clearance (P = 0.003). No SNPs were associated with CY clearance or the ratio of 4HCY/CY AUC after controlling for a false discovery rate.
Conclusion: Age and chemotherapy regimen, but not germline pharmacogenomics, were associated with CY clearance or the ratio of 4HCY/CY AUC. Other methods, such as metabolomics or lipidomics, should be explored.
(© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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R01 GM129863 United States GM NIGMS NIH HHS; R03 CA178104 United States CA NCI NIH HHS; M01 RR000037 United States RR NCRR NIH HHS; R21 CA162059 United States CA NCI NIH HHS; R01 HL091744 United States HL NHLBI NIH HHS

8N3DW7272P (Cyclophosphamide)
1XBF4E50HS (4-hydroxycyclophosphamide)

Date Created: 20240730 Date Completed: 20240928 Latest Revision: 20240930

20240930

PMC11438565

10.1007/s00280-024-04703-2

39080017