title: Performance of modified-release tacrolimus after conversion in liver transplant patients indicates potentially favorable outcomes in selected cohorts.
abstract: Clinical outcomes, dose changes, and dose-equalized tacrolimus concentrations were examined sequentially in 129 liver transplantation (LT) recipients after successful conversion to once daily modified-release tacrolimus either early (within 1 month) or late (>1 month) after LT. The data were compared with data for a group of 60 patients maintained on twice daily conventional-release tacrolimus. Formulation- and time-dependent changes in dose requirements for once and twice daily tacrolimus differed after transplantation. A 1.7-fold initial increase in the median daily dose was required to achieve target tacrolimus concentrations in the early-conversion cohort (P = 0.006), whereas a 1.25-fold increase was required for those converted later (P = 0.013 and P < 0.001 for the difference). In the subsequent 2 months, the median daily dose fell by 20% in the early-conversion cohort, remained stable for the late-conversion cohort, but rose by 33% with conventional therapy. Lower median dose-equalized concentrations persisted for up to 3 months after the conversion to modified-release therapy. Sex, ethnicity, and the underlying liver disease did not significantly affect these variables. The frequency of treated biopsy-proven acute rejection episodes fell approximately 4-fold after the conversion to modified-release tacrolimus, most notably in the late-conversion cohort, which experienced a high incidence of rejection before conversion. Posttransplant increases in serum creatinine concentrations were smaller after the introduction of modified-release tacrolimus in the late-conversion group (0.7 versus 4 mg/mL for twice daily tacrolimus over 6 months). Reduced interpatient variability in tacrolimus concentrations was evident in the early-conversion cohort versus the twice daily cohort. A decline in intrapatient variability accompanied the reduction in acute rejection in the late-conversion cohort. Our data highlight potential benefits for the rejection rate and renal function on conversion to once daily modified-release tacrolimus late after LT.
authors.affiliation: Department of Pharmacy; Institute of Pharmaceutical Sciences.
authors.forename: Aisling
authors.initials: A
authors.lastname: Considine
authors.forename: J Michael
authors.initials: JM
authors.lastname: Tredger
authors.forename: Michael
authors.initials: M
authors.lastname: Heneghan
authors.forename: Kosh
authors.initials: K
authors.lastname: Agarwal
authors.forename: Marianne
authors.initials: M
authors.lastname: Samyn
authors.forename: Nigel D
authors.initials: ND
authors.lastname: Heaton
authors.forename: John G
authors.initials: JG
authors.lastname: O'Grady
authors.forename: Varuna R
authors.initials: VR
authors.lastname: Aluvihare
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D003404:Creatinine / Q000097:blood; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D057915:Drug Substitution; D005260:Female; D006084:Graft Rejection / Q000175:diagnosis / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology; D016031:Liver Transplantation / Q000009:adverse effects; D008131:London; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D012307:Risk Factors; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; D003692:Delayed-Action Preparations; D007166:Immunosuppressive Agents; D003404:Creatinine; D016559:Tacrolimus