title: Pharmacokinetics of prolonged-release tacrolimus versus immediate-release tacrolimus in de novo liver transplantation: A randomized phase III substudy.
abstract: With the same dose of tacrolimus, lower systemic exposure on the first day of dosing has been reported for prolonged-release tacrolimus compared with immediate-release tacrolimus, prompting investigation of differing initial doses.
  
  
  
  This substudy of a double-blind, randomized, phase III trial in de novo liver transplant recipients compared the pharmacokinetics of once-daily prolonged-release tacrolimus (initial dose: 0.2 mg/kg/day) versus twice-daily immediate-release tacrolimus (initial dose: 0.1 mg/kg/day) during the first 2 weeks post-transplant.
  
  
  
  Pharmacokinetic data were analyzed from patients receiving prolonged-release tacrolimus (n=13) and immediate-release tacrolimus (n=12). Mean systemic exposure (AUC0-24) was higher with prolonged-release versus immediate-release tacrolimus. Dose-normalized AUC0-24(normalized to 0.1 mg/kg/day) showed generally lower exposure with prolonged-release tacrolimus versus immediate-release tacrolimus. There was good correlation between AUC0-24and concentration at 24 hours after the morning dose (r=.96 and r=.86, respectively), and the slope of the line of best fit was similar for both formulations.
  
  
  
  Doubling the initial starting dose of prolonged-release tacrolimus compared with immediate-release tacrolimus overcompensated for lower exposure on Day 1. A 50% higher starting dose of prolonged-release tacrolimus than immediate-release tacrolimus may be required for similar systemic exposure. However, doses of both formulations can be optimized using the same trough-level monitoring system. (ClinicalTrials.gov number: NCT00189826).
authors.affiliation: Division of Transplantation Surgery, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Bo-Göran
authors.initials: BG
authors.lastname: Ericzon
authors.affiliation: Liver Transplant Unit, University Hospital Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: Evaristo
authors.initials: E
authors.lastname: Varo
authors.affiliation: Transplantcentre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Trunečka
authors.affiliation: Department of Hepatobiliary and Transplant Surgery, University Medical Center, Hamburg-Eppendorf, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Fischer
authors.affiliation: Department of Surgery, Ospedale Giovanni XXIII, Bergamo, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Colledan
authors.affiliation: Division of Abdominal and Transplantation Surgery, ISMETT, Palermo, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Gridelli
authors.affiliation: Liver Transplant Unit, Cruces University Hospital, Baracaldo-Bilbao, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Valdivieso
authors.affiliation: Liver Transplant Unit, King's College Hospital, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: O'Grady
authors.affiliation: Clinical Services, NUVISAN GmbH, Neu-Ulm, Germany.
authors.forename: James
authors.initials: J
authors.lastname: Dickinson
authors.affiliation: Medical affairs, Astellas Pharma Europe Ltd, Chertsey, UK.
authors.forename: Nasrullah
authors.identifier: 0000-0001-7294-7883
authors.initials: N
authors.lastname: Undre
mesh_terms: D019540:Area Under Curve; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011379:Prognosis; D012307:Risk Factors; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus
keywords: calcineurin inhibitor; immunosuppressant; liver transplantation; living donor; pharmacokinetics/pharmacodynamics; rejection; tacrolimus