title: Which Genetic Determinants Should be Considered for Tacrolimus Dose Optimization in Kidney Transplantation? A Combined Analysis of Genes Affecting the CYP3A Locus.
abstract: BACKGROUND
  Tacrolimus is established as immunosuppressant after kidney transplantation. Polymorphism of the cytochrome P450 3A5 (CYP3A5) gene contributes significantly to tacrolimus dose requirements. Recently, CYP3A4*22 was reported to additionally affect tacrolimus pharmacokinetics (PK). In addition, there are further polymorphic genes, possibly influencing CYP3A activity [pregnane x receptor NR1I2, P450 oxidoreductase (POR), and peroxisome proliferator-activator receptor alpha (PPARA)]. We aimed to investigate combined effects of these gene variants on tacrolimus maintenance dose and PK in patients with stable kidney transplantation of 2 study centers.
  
  
  METHODS
  A total of 223 white patients (German cohort, 136; Danish cohort, 87) was included and genotyped for CYP3A5 (rs776746), CYP3A4 (rs35599367), NR1I2 (rs2276707), POR (rs1057868), and PPARA (rs4253728). Dosage and trough concentration/dose ratios were considered separately. A subset was investigated for comprehensive PK parameters.
  
  
  RESULTS
  Tacrolimus dose, trough concentration, and trough concentration/dose ratio did not differ between the German and Danish cohort. CYP3A5*3 and CYP3A4*22 contributed to dose requirements only in the German and in the total cohort. Homozygous carriers of both variants required 4.8 ± 3.1 mg, whereas carriers of the wild types required 165% higher mean tacrolimus doses (12.5 ± 7.7 mg, P = 1.4 × 10). The PK investigation revealed only nonsignificant impact of CYP3A4 genotypes on AUC12h in CYP3A5 nonexpressers (P = 0.079, power = 57%). For the entire sample, the final multiple linear regression model for trough concentration/dose ratio included CYP3A5, CYP3A4, and age. It explained 18.3% of the interindividual variability of tacrolimus trough concentration/dose ratios (P = 8.8 × 10).
  
  
  CONCLUSIONS
  Therapeutic drug monitoring remains essential in clinical care of patients with kidney transplantation. Genotyping of CYP3A5 and CYP3A4, however, could facilitate rapid dose finding to adapt the appropriate immunosuppressant dose, whereas other genetic factors had only little or no effect.
authors.affiliation: *Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel; †Department of Nephrology, University Hospital Rechts der Isar, Technical University of Munich; ‡Department of Nephrology and Hypertension, University Hospital Schleswig-Holstein, Campus Kiel, Germany; §Department of Nephrology, Odense University Hospital, Institute of Molecular Medicine, Institute of Clinical Research, University of Southern Denmark, Odense; and ¶Institute of Medical Informatics and Statistics, University Hospital Schleswig-Holstein, Campus Kiel, Germany.
authors.forename: Henrike
authors.initials: H
authors.lastname: Bruckmueller
authors.forename: Anneke Nina
authors.initials: AN
authors.lastname: Werk
authors.forename: Lutz
authors.initials: L
authors.lastname: Renders
authors.forename: Thorsten
authors.initials: T
authors.lastname: Feldkamp
authors.forename: Martin
authors.initials: M
authors.lastname: Tepel
authors.forename: Christoffer
authors.initials: C
authors.lastname: Borst
authors.forename: Amke
authors.initials: A
authors.lastname: Caliebe
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kunzendorf
authors.forename: Ingolf
authors.initials: I
authors.lastname: Cascorbi
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D008875:Middle Aged; D047493:PPAR alpha / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D007166:Immunosuppressive Agents; C000625852:NR1I2 protein, human; C000602470:POR protein, human; D047493:PPAR alpha; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus