CONVERSION OF STABLE LIVER TRANSPLANT RECIPIENTS FROM A TWICE DAILY PROGRAF BASED REGIMEN TO A ONCE DAILY MODIFIED RELEASE TACROLIMUS BASED REGIMEN

Abstract

O305 Aims: Modified Release (MR) tacrolimus is an extended release formulation of tacrolimus administered once daily (QD). Data from healthy volunteer studies indicate that the MR formulation given QD and Prograf administered twice daily (BID) have similar exposure (AUC0-24) and that MR has similar, or stronger correlation between AUC and Cmin (trough). The purpose of this pharmacokinetic (PK) study was to evaluate tacrolimus exposure and trough levels in stable liver transplant recipients converted from Prograf to MR in a single sequence, four period crossover study design. Methods: This was an open label, multi-center study to determine and compare the PK of tacrolimus in 70 stable liver transplant recipients. Eligible patients were 18 to 65 years who had received a liver transplant at least six months prior to enrollment, who were receiving stable doses of Prograf for more than 2 weeks prior to enrollment and who had stable renal function (defined by serum creatinine <2.0 mg/dL) prior to enrollment. Patients receiving sirolimus therapy or any other drug interfering with tacrolimus metabolism, or experiencing abnormal liver function (defined as AST or ALT >2x the upper limit of normal) or any patient experiencing rejection episodes requiring antibody therapy in the last six months were excluded from this study. Patients received Prograf BID on Days 1-14 and Days 29-42. Patients were converted to the same milligram-for-milligram daily dose of MR QD on Days 15-28 and Days 43-56. Twenty-four hour PK profiles were obtained on Days 14, 28, 42 and 56. Laboratory and safety parameters were also evaluated. Results: The AUC(0-24) of tacrolimus was comparable for Prograf (Days 14 and 42) and MR (Days 28 and 56) within the equivalence range of 80-125%. The 90% confidence intervals (CI) for the MR versus Prograf comparison at steady state (Days 28 and 56 vs. Days 14 and 42) was 0.85 to 0.92 for AUC(0-24). MR was well tolerated, with a safety profile comparable to that of Prograf. AUC(0-24) was highly correlated to Cmin for Prograf (Day 14 r=0.94; Day 42 r=0.86) and MR (Day 28 r=0.90, Day 56 r=0.88). Renal and liver function remained stable throughout the study and 62/70 patients completed all four PK profiles. Conclusions: The steady-state tacrolimus exposure of MR is equivalent to Prograf after a milligram-for-milligram conversion in stable liver transplant recipients.