title: Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia.
abstract: BACKGROUND
  This study evaluates the relationship between cytochrome P450 (CYP) 3A5 genotype and vincristine-induced peripheral neuropathy (VIPN) in children with precursor B cell acute lymphoblastic leukemia (preB ALL). We have shown in vitro that vincristine is metabolized significantly more efficiently by CYP3A5 than by CYP3A4. We also found that vincristine neurotoxicity is less common in African-Americans (70% express CYP3A5) than in Caucasians. We test the hypothesis that CYP3A5 expressers experience less vincristine neuropathy than do CYP3A5 non-expressers.
  
  
  METHODS
  This study of pharmacogenetics of vincristine neuropathy in children with preB ALL was completed at Indiana University Simon Cancer Center. Whole blood for DNA extraction and genotyping was collected as well as plasma from a single time-point for analysis of vincristine and primary metabolite (M1) concentrations. Vincristine neuropathy was captured via chart review and graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.
  
  
  RESULTS
  Eighty-nine percent of CYP3A5 expressers experienced neurotoxicity versus 100% of non-expressers (P = 0.03). The proportion of treatment months with neurotoxicity was significantly different between the expressers and non-expressers (16% vs. 27%, P = 0.0007). Limited pharmacokinetic data suggest different rates of vincristine metabolism between CYP3A5 genotype groups with higher primary metabolite (M1) plasma concentrations (P = 0.0004) and lower metabolic ratios ([vincristine]/[M1]) (P = 0.036) in the CYP3A5 expressers compared to the CYP3A5 non-expressers. M1 concentration was also inversely related to severity of neuropathy (P = 0.0316).
  
  
  CONCLUSIONS
  In children with preB ALL, CYP3A5 expressers experience less VIPN, produce more M1, and have lower metabolic ratios compared to CYP3A5 non-expressers.
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Akinbode
authors.initials: A
authors.lastname: Egbelakin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ferguson
authors.forename: Emily A
authors.initials: EA
authors.lastname: MacGill
authors.forename: Amalia S
authors.initials: AS
authors.lastname: Lehmann
authors.forename: Ariel R
authors.initials: AR
authors.lastname: Topletz
authors.forename: Sara K
authors.initials: SK
authors.lastname: Quinney
authors.forename: Lang
authors.initials: L
authors.lastname: Li
authors.forename: Kevin C
authors.initials: KC
authors.lastname: McCammack
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hall
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Renbarger
mesh_terms: D000293:Adolescent; D001741:Black or African American; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D005838:Genotype; D006801:Humans; D007223:Infant; D008657:Metabolic Clearance Rate; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D010597:Pharmacogenetics; D016133:Polymerase Chain Reaction; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics*; D014018:Tissue Distribution; D014750:Vincristine / Q000009:adverse effects* / Q000493:pharmacokinetics; D044465:White People
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004273:DNA, Neoplasm; D014750:Vincristine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A