title: Kidney transplant outcomes are related to tacrolimus, mycophenolic acid and prednisolone exposure in the first week.
abstract: This study analysed associations between tacrolimus, mycophenolic acid (MPA) and prednisolone exposures on day 4 and month 1 post kidney transplant and clinical outcomes. Area under the concentration-time curve (AUC) for each drug was estimated using validated multiple regression-derived limited sampling strategies. Multivariate logistic regression was used to associate drug exposure with clinical outcomes. One hundred and twenty subjects were studied. Between-subject variability in dose-adjusted exposure to each medication was high. Both day 4 tacrolimus and MPA exposures were independently predictive of delayed graft function (2.6 change in odds for a standard deviation (SD) increase in tacrolimus AUC(0-12) , P = 0.02; 0.23 change in odds for a SD increase in MPA AUC(0-12) , P = 0.02). Both day 4 MPA and total prednisolone exposures were independently predictive of rejection (0.20 change in odds for a SD increase in MPA AUC(0-12) , P = 0.04; 0.40 change in odds for a SD increase in total prednisolone AUC(0-6) , P = 0.03). Lowest tertile exposure to all three immunosuppressant medications imposed significantly higher odds of rejection [adjusted odds ratio 34.2 (95% CI 4.1, 284.4), P = 0.001]. This study highlights the importance of achieving early target exposure and suggests a potential role for individualized initial dosing or early therapeutic monitoring of all three immunosuppressive agents.
authors.affiliation: Department of Nephrology, University of Queensland at the Princess Alexandra Hospital, Brisbane, Qld, Australia. arbieb@hotmail.com
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Barraclough
authors.forename: Christine E
authors.initials: CE
authors.lastname: Staatz
authors.forename: David W
authors.initials: DW
authors.lastname: Johnson
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Lee
authors.forename: Brett C
authors.initials: BC
authors.lastname: McWhinney
authors.forename: Jacobus Pj
authors.initials: JP
authors.lastname: Ungerer
authors.forename: Carmel M
authors.initials: CM
authors.lastname: Hawley
authors.forename: Scott B
authors.initials: SB
authors.lastname: Campbell
authors.forename: Diana R
authors.initials: DR
authors.lastname: Leary
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Isbel
mesh_terms: D000328:Adult; D019540:Area Under Curve; D051799:Delayed Graft Function / Q000188:drug therapy / Q000209:etiology; D005260:Female; D006084:Graft Rejection / Q000209:etiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011239:Prednisolone / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016559:Tacrolimus / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D011239:Prednisolone; D009173:Mycophenolic Acid; D016559:Tacrolimus