title: Lower variability in 24-hour exposure during once-daily compared to twice-daily tacrolimus formulation in kidney transplantation.
abstract: BACKGROUND
  Tacrolimus has originally been registered as a twice-daily formulation (Prograf, Tac BID), although a once-daily formulation (Advagraf, Tac QD) is also available. A reduced intrapatient variability of Tac Cmin, a surrogate marker for 24-hour drug exposure (AUC0-24), has been suggested. The variability of AUC0-24 has never been studied prospectively yet. The purpose of this study was to investigate the change in intrapatient variability of Tac AUC0-24 after converting from Tac BID to Tac QD.
  
  
  METHODS
  Forty renal transplant patients on Tac BID were converted on a 1:1 (mg/mg) basis to Tac QD in an investigator-driven comparative pharmacokinetic (PK) study. AUC0-24 was determined five times before and after conversion. Duplicate samples were collected by the patients themselves using the dried blood spot method. The main outcome measure is the change in intrapatient variability of AUC0-24 expressed as coefficient of variation (CV). Moreover, the influence of Cyp3A5 genotype polymorphism on the change in CV was studied.
  
  
  RESULTS
  In total, 400 AUC0-24 profiles were available for analysis. Conversion to Tac QD resulted in a significant improvement in intra-patient CV from 14.1% to 10.9% (P=0.012). Patients with the Cyp3A5*1/*3 genotype (n=11) had a numerically larger improvement in CV than patients with the CYP3A5*3/*3 genotype.
  
  
  CONCLUSIONS
  Intrapatient CV of Tac AUC0-24 improved after converting from Tac BID to Tac QD in stable renal transplant patients, especially in patients with the CYP3A5*1/3 genotype. Given the very strict protocol of this PK study, this improvement is most likely due to the different intrinsic PK properties of Tac QD and Tac BID.
authors.affiliation: 1 Department of Internal Medicine, Division of Nephrology, Maastricht University Medical Centre, Maastricht, The Netherlands. 2 Department of Clinical Pharmacology and Toxicology, Maastricht University Medical Centre, Maastricht, The Netherlands. 3 Astellas Pharma Europe Ltd., Chertsey, United Kingdom. 4 Address correspondence to: Maarten H.L. Christiaans, Department of Internal Medicine, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Stifft
authors.forename: Leo M L
authors.initials: LM
authors.lastname: Stolk
authors.forename: Nasrullah
authors.initials: N
authors.lastname: Undre
authors.forename: Johannes P
authors.initials: JP
authors.lastname: van Hooff
authors.forename: Maarten H L
authors.initials: MH
authors.lastname: Christiaans
mesh_terms: D000328:Adult; D000368:Aged; D002626:Chemistry, Pharmaceutical; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus