title: Dosing equation for tacrolimus using genetic variants and clinical factors.
abstract: OBJECTIVE
  To develop a dosing equation for tacrolimus, using genetic and clinical factors from a large cohort of kidney transplant recipients. Clinical factors and six genetic variants were screened for importance towards tacrolimus clearance (CL/F).
  
  
  METHODS
  Clinical data, tacrolimus troughs and corresponding doses were collected from 681 kidney transplant recipients in a multicentre observational study in the USA and Canada for the first 6 months post transplant. The patients were genotyped for 2,724 single nucleotide polymorphisms using a customized Affymetrix SNP chip. Clinical factors and the most important SNPs (rs776746, rs12114000, rs3734354, rs4926, rs3135506 and rs2608555) were analysed for their influence on tacrolimus CL/F.
  
  
  RESULTS
  The CYP3A5*1 genotype, days post transplant, age, transplant at a steroid sparing centre and calcium channel blocker (CCB) use significantly influenced tacrolimus CL/F. The final model describing CL/F (l h(-1)) was: 38.4 ×[(0.86, if days 6-10) or (0.71, if days 11-180)]×[(1.69, if CYP3A5*1/*3 genotype) or (2.00, if CYP3A5*1/*1 genotype)]× (0.70, if receiving a transplant at a steroid sparing centre) × ([age in years/50](-0.4)) × (0.94, if CCB is present). The dose to achieve the desired trough is then prospectively determined using the individuals CL/F estimate.
  
  
  CONCLUSIONS
  The CYP3A5*1 genotype and four clinical factors were important for tacrolimus CL/F. An individualized dose is easily determined from the predicted CL/F. This study is important towards individualization of dosing in the clinical setting and may increase the number of patients achieving the target concentration. This equation requires validation in an independent cohort of kidney transplant recipients.
authors.affiliation: Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Chaitali
authors.initials: C
authors.lastname: Passey
authors.forename: Angela K
authors.initials: AK
authors.lastname: Birnbaum
authors.forename: Richard C
authors.initials: RC
authors.lastname: Brundage
authors.forename: William S
authors.initials: WS
authors.lastname: Oetting
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Israni
authors.forename: Pamala A
authors.initials: PA
authors.lastname: Jacobson
mesh_terms: D000328:Adult; D002170:Canada; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014481:United States
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus