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Influence of CYP3A5 genetic variation on everolimus maintenance dosing after cardiac transplantation.

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  • معلومة اضافية
    • المصدر:
      Publisher: Munksgaard Country of Publication: Denmark NLM ID: 8710240 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1399-0012 (Electronic) Linking ISSN: 09020063 NLM ISO Abbreviation: Clin Transplant Subsets: MEDLINE
    • بيانات النشر:
      Original Publication: Copenhagen : Munksgaard,
    • الموضوع:
      Cytochrome P-450 CYP3A/*genetics ; Everolimus/*administration & dosage ; Graft Rejection/*genetics ; Heart Transplantation/*adverse effects ; Polymorphism, Genetic/*genetics; Adolescent ; Adult ; Aged ; Dose-Response Relationship, Drug ; Female ; Follow-Up Studies ; Graft Rejection/drug therapy ; Graft Survival ; Humans ; Immunosuppressive Agents/administration & dosage ; Maintenance Chemotherapy ; Male ; Middle Aged ; Pilot Projects ; Postoperative Complications ; Prognosis ; Risk Factors ; Young Adult
    • نبذة مختصرة :
      Background: Everolimus (ERL) has become an alternative to calcineurin inhibitors (CNIs) due to its renal-sparing properties, especially in heart transplant (HTx) recipients with kidney dysfunction. However, ERL dosing is challenging due to its narrow therapeutic window combined with high interindividual pharmacokinetic variability. Our aim was to evaluate the effect of clinical and genetic factors on ERL dosing in a pilot cohort of 37 HTx recipients.
      Methods: Variants in CYP3A5, CYP3A4, CYP2C8, POR, NR1I2, and ABCB1 were genotyped, and clinical data were retrieved from patient charts.
      Results: While ERL trough concentration (C0 ) was within the targeted range for most patients, over 30-fold variability in the dose-adjusted ERL C0 was observed. Regression analysis revealed a significant effect of the non-functional CYP3A5*3 variant on the dose-adjusted ERL C0 (p = 0.031). ERL dose requirement was 0.02 mg/kg/d higher in patients with CYP3A5*1/*3 genotype compared to patients with CYP3A5*3/*3 to reach the targeted C0 (p = 0.041). ERL therapy substantially improved estimated glomerular filtration rate (28.6 ± 6.6 mL/min/1.73 m(2)) in patients with baseline kidney dysfunction.
      Conclusion: Everolimus pharmacokinetics in HTx recipients is highly variable. Our preliminary data on patients on a CNI-free therapy regimen suggest that CYP3A5 genetic variation may contribute to this variability.
      (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
    • Contributed Indexing:
      Keywords: CYP3A5*3; everolimus; heart transplantation; pharmacogenomics
    • الرقم المعرف:
      0 (Immunosuppressive Agents)
      9HW64Q8G6G (Everolimus)
      EC 1.14.14.1 (CYP3A5 protein, human)
      EC 1.14.14.1 (Cytochrome P-450 CYP3A)
    • الموضوع:
      Date Created: 20151014 Date Completed: 20161027 Latest Revision: 20161230
    • الموضوع:
      20240628
    • الرقم المعرف:
      10.1111/ctr.12653
    • الرقم المعرف:
      26458301