title: Influence of CYP3A5 genetic variation on everolimus maintenance dosing after cardiac transplantation.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Clinical Chemistry, University Hospital (Inselspital Bern), University of Bern, Bern, Switzerland.|Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Lesche
authors.affiliation: Department of Cardiology, Bern, Switzerland.
authors.forename: Vilborg
authors.initials: V
authors.lastname: Sigurdardottir
authors.affiliation: Department of Cardiology, Bern, Switzerland.
authors.forename: Raschid
authors.initials: R
authors.lastname: Setoud
authors.affiliation: Department of Cardiovascular Surgery, Swiss Cardiovascular Centre, University Hospital (Inselspital Bern), Bern, Switzerland.
authors.forename: Lars
authors.initials: L
authors.lastname: Englberger
authors.affiliation: Institute of Clinical Chemistry, University Hospital (Inselspital Bern), University of Bern, Bern, Switzerland.
authors.forename: Georg M
authors.initials: GM
authors.lastname: Fiedler
authors.affiliation: Institute of Clinical Chemistry, University Hospital (Inselspital Bern), University of Bern, Bern, Switzerland.
authors.forename: Carlo R
authors.initials: CR
authors.lastname: Largiadèr
authors.affiliation: Department of Cardiology, Bern, Switzerland.
authors.forename: Paul
authors.initials: P
authors.lastname: Mohacsi
authors.affiliation: Institute of Clinical Chemistry, University Hospital (Inselspital Bern), University of Bern, Bern, Switzerland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Sistonen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus / Q000008:administration & dosage*; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000188:drug therapy / Q000235:genetics*; D006085:Graft Survival; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011110:Polymorphism, Genetic / Q000235:genetics*; D011183:Postoperative Complications; D011379:Prognosis; D012307:Risk Factors; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D000068338:Everolimus; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A
keywords: CYP3A5*3; everolimus; heart transplantation; pharmacogenomics