title: A high intrapatient variability in tacrolimus exposure is associated with poor long-term outcome of kidney transplantation.
abstract: Tacrolimus is a critical dose drug with a considerable intrapatient variability (IPV) in its pharmacokinetics. We investigated whether a high IPV in tacrolimus exposure is associated with adverse long-term renal transplantation outcomes. Tacrolimus IPV was calculated from predose concentrations measured between 6 and 12 months post-transplantation of 808 renal transplant recipients (RTRs) transplanted between 2000 and 2010. One hundred and eighty-eight (23.3%) patients reached the composite end point consisting of graft loss, late biopsy-proven rejection, transplant glomerulopathy, or doubling of serum creatinine concentration between month 12 and the last follow-up. The cumulative incidence of the composite end point was significantly higher in patients with high IPV than in patients with low IPV (hazard ratio: 1.41, 95% CI: 1.06-1.89; P = 0.019). After the adjustment for several factors, the higher incidence of the composite end point for RTRs with a high IPV remained statistically significant (hazard ratio: 1.42, 95% CI: 1.06-1.90; P = 0.019). Younger recipient age at transplantation, previous transplantation, worse graft function (at month 6 post-transplantation), and low mean tacrolimus concentration at 1 year post-transplantation were additional predictors for worse long-term transplant outcome. A high tacrolimus IPV is an independent risk factor for adverse kidney transplant outcomes that can be used as an easy monitoring tool to help identify high-risk RTRs.
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. n.shuker@erasmusmc.nl.|Department of Hospital Pharmacy, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. n.shuker@erasmusmc.nl.
authors.forename: Nauras
authors.initials: N
authors.lastname: Shuker
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Lamis
authors.initials: L
authors.lastname: Shuker
authors.affiliation: Department of Biostatistics, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: van Rosmalen
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Joke I
authors.initials: JI
authors.lastname: Roodnat
authors.affiliation: Department of Hospital Pharmacy, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Lennaert C P
authors.initials: LC
authors.lastname: Borra
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Willem
authors.initials: W
authors.lastname: Weimar
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Hesselink
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.|Department of Hospital Pharmacy, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Teun
authors.initials: T
authors.lastname: van Gelder
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001706:Biopsy; D003404:Creatinine / Q000097:blood; D005260:Female; D006084:Graft Rejection / Q000097:blood; D006801:Humans; D007118:Immunoassay; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D051437:Renal Insufficiency / Q000601:surgery*; D015203:Reproducibility of Results; D012189:Retrospective Studies; D012307:Risk Factors; D016559:Tacrolimus / Q000008:administration & dosage*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D003404:Creatinine; D016559:Tacrolimus
keywords: intrapatient variability; kidney transplantation; tacrolimus; therapeutic drug monitoring; transplant survival