title: CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity.
abstract: OBJECTIVE
  Paclitaxel is used for the treatment of several solid tumors and displays a high interindividual variation in exposure and toxicity. Neurotoxicity is one of the most prominent side effects of paclitaxel. This study explores potential predictive pharmacokinetic and pharmacogenetic determinants for the onset and severity of neurotoxicity.
  
  
  METHODS
  In an exploratory cohort of patients (n = 261) treated with paclitaxel, neurotoxicity incidence, and severity, pharmacokinetic parameters and pharmacogenetic variants were determined. Paclitaxel plasma concentrations were measured by high-performance liquid chromatography or liquid chromatography/tandem mass spectrometry, and individual pharmacokinetic parameters were estimated from previously developed population pharmacokinetic models by nonlinear mixed effects modeling. Genetic variants of paclitaxel pharmacokinetics tested were CYP3A4*22, CYP2C8*3, CYP2C8*4, and ABCB1 3435 C>T. The association between CYP3A4*22 and neurotoxicity observed in the exploratory cohort was validated in an independent patient cohort (n = 239).
  
  
  RESULTS
  Exposure to paclitaxel (logAUC) was correlated with severity of neurotoxicity (P < 0.00001). Female CYP3A4*22 carriers were at increased risk of developing neurotoxicity (P = 0.043) in the exploratory cohort. CYP3A4*22 carrier status itself was not associated with pharmacokinetic parameters (CL, AUC, Cmax, or T>0.05) of paclitaxel in males or females. Other genetic variants displayed no association with neurotoxicity. In the subsequent independent validation cohort, CYP3A4*22 carriers were at risk of developing grade 3 neurotoxicity (OR = 19.1; P = 0.001).
  
  
  CONCLUSIONS
  Paclitaxel exposure showed a relationship with the severity of paclitaxel-induced neurotoxicity. In this study, female CYP3A4*22 carriers had increased risk of developing severe neurotoxicity during paclitaxel therapy. These observations may guide future individualization of paclitaxel treatment.
authors: Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors: Anne-Joy M
authors: AJ
authors: de Graan
authors: Laure
authors: L
authors: Elens
authors: Jason A
authors: JA
authors: Sprowl
authors: Alex
authors: A
authors: Sparreboom
authors: Lena E
authors: LE
authors: Friberg
authors: Bronno
authors: B
authors: van der Holt
authors: Pleun J
authors: PJ
authors: de Raaf
authors: Peter
authors: P
authors: de Bruijn
authors: Frederike K
authors: FK
authors: Engels
authors: Ferry A L M
authors: FA
authors: Eskens
authors: Erik A C
authors: EA
authors: Wiemer
authors: Jaap
authors: J
authors: Verweij
authors: Ron H J
authors: RH
authors: Mathijssen
authors: Ron H N
authors: RH
authors: van Schaik
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000235:genetics; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects; D020641:Polymorphism, Single Nucleotide; D012727:Sex Characteristics
chemical_list: D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017239:Paclitaxel
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