title: Pharmacokinetics for once-daily versus twice-daily tacrolimus formulations in de novo liver transplantation: a randomized, open-label trial.
abstract: Tacrolimus, a cornerstone immunosuppressant, is available as a twice-daily formulation (tacrolimus bid). A once-daily prolonged-release formulation (tacrolimus qd) has been developed. This 6-week, randomized, phase 2, multicenter, open-label, prospective trial in primary liver transplant recipients investigated and compared the pharmacokinetics (PK) of tacrolimus for qd and bid formulations. All patients received tacrolimus-based immunosuppression (tacrolimus qd, n = 67; bid, n = 62). PK data were available for 77 patients (tacrolimus qd, n = 45; bid, n = 32). Tacrolimus area under the curve (AUC) from 0 to 24 hours (AUC(0-24) ) at equivalent doses was approximately 50% lower for tacrolimus qd than for bid on day 1 (146 versus 264 ng · h/mL, respectively), but by day 14 was comparable between treatments (324 and 287 ng · h/mL, respectively) with higher tacrolimus qd doses. There was a strong correlation between AUC(0-24) and concentration at 24 hours for tacrolimus qd and bid (r = 0.92 and r = 0.76, respectively). Furthermore, the relationship between these 2 parameters (ie, the slope of the line) was also similar for the 2 formulations. Efficacy endpoints were comparable for both formulations at 6 weeks with no marked differences in incidence, nature, or severity of adverse events between treatments (although the study was not powered to draw efficacy conclusions). These results suggest that targeting the same trough levels will achieve similar total AUC over 24 hours for both tacrolimus qd and tacrolimus bid in de novo liver transplant recipients.
authors.affiliation: Department of Hepatobiliary Surgery and Transplantation, Universitat Krankenhaus Eppendorf, Hamburg, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Fischer
authors.forename: Pavel
authors.initials: P
authors.lastname: Trunečka
authors.forename: Bruno
authors.initials: B
authors.lastname: Gridelli
authors.forename: Andre
authors.initials: A
authors.lastname: Roy
authors.forename: Alessandro
authors.initials: A
authors.lastname: Vitale
authors.forename: Andrés
authors.initials: A
authors.lastname: Valdivieso
authors.forename: Evaristo
authors.initials: E
authors.lastname: Varo
authors.forename: Daniel
authors.initials: D
authors.lastname: Seehofer
authors.forename: Stephen
authors.initials: S
authors.lastname: Lynch
authors.forename: Didier
authors.initials: D
authors.lastname: Samuel
authors.forename: Bo-Goran
authors.initials: BG
authors.lastname: Ericzon
authors.forename: Karim
authors.initials: K
authors.lastname: Boudjema
authors.forename: Carmen
authors.initials: C
authors.lastname: Karpf
authors.forename: Nasrullah
authors.initials: N
authors.lastname: Undre
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001315:Australia; D002170:Canada; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005060:Europe; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D053208:Kaplan-Meier Estimate; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D013810:Therapeutic Equivalency; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D003692:Delayed-Action Preparations; D007166:Immunosuppressive Agents; D016559:Tacrolimus