title: Population pharmacokinetics and pharmacogenetics of once daily tacrolimus formulation in stable liver transplant recipients.
abstract: OBJECTIVE
  The once daily formulation of tacrolimus is an important immunosuppressive drug. Interpatient variability in metabolism has been related to genetic variation in CYP3A4 and CYP3A5. However, in liver transplantation, both donor and recipient genotypes may affect pharmacokinetics. The primary objective of this study was to investigate the effect of CYP3A4*22 and CYP3A5*3 of both donor and recipient on once daily tacrolimus pharmacokinetics. The secondary objective was to develop a limited sampling model able to accurately predict exposure.
  
  
  METHODS
  Stable liver transplant patients receiving once daily tacrolimus (N = 66) were included. Population pharmacokinetic analysis was performed with patients of whom DNA was available (N = 49), and demographic factors, CYP3A4*22 and CYP3A5*3, were tested as covariates. Moreover, a limited sampling model was developed using data of 66 patients.
  
  
  RESULTS
  Pharmacokinetics was best described by a two-compartment model with delayed absorption. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 carrying liver had an average 1.7-fold higher clearance compared to non-carriers. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 non-carrying liver or vice versa showed an average 1.3-fold higher clearance compared with non-carriers. CYP3A4*22 was not significantly associated with once daily tacrolimus pharmacokinetics. Using 0, 2, and 3 h postdose as limited sampling model resulted in significantly improved prediction of tacrolimus exposure compared with trough concentration.
  
  
  CONCLUSIONS
  Both donor and recipient CYP3A5 genotype significantly influences tacrolimus once daily pharmacokinetics. In contrast, CYP3A4*22 appears not suitable as biomarker. The developed limited sampling model can be used to accurately estimate tacrolimus once daily exposure.
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. d.j.a.r.moes@lumc.nl.
authors.forename: D J A R
authors.initials: DJ
authors.lastname: Moes
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: S A S
authors.initials: SA
authors.lastname: van der Bent
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Swen
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: van der Straaten
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Inderson
authors.affiliation: Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Olofsen
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: H W
authors.initials: HW
authors.lastname: Verspaget
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.
authors.forename: H J
authors.initials: HJ
authors.lastname: Guchelaar
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: den Hartigh
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: van Hoek
mesh_terms: D000328:Adult; D000368:Aged; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004334:Drug Administration Schedule; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014019:Tissue Donors
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus
keywords: Advagraf; Liver transplantation; Once daily tacrolimus; Pharmacogenetics; Population pharmacokinetics