title: Combined effects of CYP3A5*1, POR*28, and CYP3A4*22 single nucleotide polymorphisms on early concentration-controlled tacrolimus exposure in de-novo renal recipients.
abstract: OBJECTIVE
  In a cohort of 298 de-novo renal recipients treated with a standard tacrolimus loading dose of 0.2 mg/kg, the combined effects of the CYP3A5*1, POR*28, and CYP3A4*22 genotypes on early tacrolimus exposure (C0), dose requirements, and achievement of the therapeutic target, C0, were examined. The incidence of clinical events (e.g. acute rejection, diabetes mellitus) was compared between genotypes.
  
  
  RESULTS
  Fast metabolizers (CYP3A5*1/POR*28T carriers) had two-fold to three-fold higher tacrolimus dose requirements compared with slow metabolizers (CYP3A5*3/*3/CYP3A4*22 carriers) and needed significantly more time to achieve the target tacrolimus C0 of a minimum 10 ng/ml (3.3±1.7 vs. 1.34±0.75 days; P<0.0001). No differences in acute rejection incidence and time to first rejection were observed. Slow metabolizers more frequently had tacrolimus C0 above the target range early after transplantation (70 vs. 13% on day 3); however, this did not translate into a higher incidence of post-transplantation diabetes mellitus or graft dysfunction. Multivariate analyses identified the CYP3A5*1/POR*28/CYP3A4*22 genotype combination as the single strongest determinant of tacrolimus dose requirements throughout the first year, explaining between 24-40% of its variability, whereas recipient age, hematocrit, and delayed graft function were additional nongenetic determinants of tacrolimus dose.
  
  
  CONCLUSIONS
  Combining the CYP3A5*1, POR*28 and CYP3A4*22 genotypes allows partial differentiation of early tacrolimus dose requirements and the time to reach therapeutic target concentrations after transplantation, but without obvious clinical implications. Larger prospective studies need to address the clinical relevance of early combined genotype-based tacrolimus dosing in de-novo renal recipients.
authors.affiliation: aDepartment of Nephrology and Renal Transplantation, University Hospitals Leuven bLaboratory of Nephrology, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors.forename: Dirk R J
authors.initials: DR
authors.lastname: Kuypers
authors.forename: Henriette
authors.initials: H
authors.lastname: de Loor
authors.forename: Maarten
authors.initials: M
authors.lastname: Naesens
authors.forename: Tamara
authors.initials: T
authors.lastname: Coopmans
authors.forename: Hylke
authors.initials: H
authors.lastname: de Jonge
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D006084:Graft Rejection / Q000188:drug therapy* / Q000209:etiology*; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: C000602470:POR protein, human; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus