Once-Daily Tacrolimus Extended-Release Formulation: 1-Year Post-Conversion in Stable Pediatric Liver Transplant Recipients

Abstract

The pharmacokinetics, safety and tolerability of a once-daily formulation of tacrolimus (tacrolimus extended-release formulation; XL formerly referred to as MR or MR4) were assessed in 18 stable pediatric liver transplant recipients who were converted from the twice-a-day formulation of tacrolimus (TAC) to XL. Patients received their twice-a-day dose of TAC on study days 1 through 7. Beginning on the morning of study day 8, patients were converted to XL on a 1:1 (mg:mg) basis for their total daily dose, and were maintained on a once-daily AM dosing regimen using the same therapeutic monitoring and patient care techniques employed with TAC. Based on pharmacokinetic profiles obtained on study days 7 (TAC) and 14 (XL), steady state exposure (AUC 0-24 ) was equivalent between XL and TAC; the mean XL/TAC ratio for lnAUC 0-24 was 100.9% (90% CI: 90.8%, 112.1%). AUC 0-24 and C min were strongly correlated at steady state (correlation coefficient: XL 0.90, TAC 0.94). During the first year post-conversion, there were no cases of acute rejection, discontinuation of XL, graft loss or death. The safety profile of XL was consistent with that known for TAC. These results support the safe and convenient conversion of pediatric liver transplant recipients from twice-a-day TAC to once-daily XL.

Conversion of Twice-Daily Tacrolimus to Once-Daily Tacrolimus Formulation in Stable Pediatric Kidney Transplant Recipients: Pharmacokinetics and Efficacy

“…In the previous pediatric liver study, Heffron et al (13) showed the difference in exposure between Tac-BID and Tac-OD was not apparent while studies for adult transplant patients consistently showed that AUC 0-24 and C min were lower for Tac-OD compared with Tac-BID (9,10). Therefore, some authors have suggested a possible modifying influence of young age on between-formulation pharmacokinetic variability (11).…”

“…In addition, a statistical analysis of AUC 0-24 and C min using total daily dose (doseadjusted) was also performed. Previous studies indicate that AUC 0-24 can be estimated at 200 AE 80 ng h/mL (8,13,20). An estimated 34 patients would be required to reach a power of 80% to show noninferiority.…”

“…Although an issue of adherence is most important in pediatric or adolescent transplant recipients, only few researches have been published on Tac-OD use in these age groups (13)(14)(15). In contrast to adult recipients, the difference in tacrolimus exposure following conversion from Tac-BID to Tac-OD was not apparent in industrydesigned phase II pharmacokinetic trial in pediatric liver transplant patients (13).…”

Effect of pharmacokinetic profile on the pancreatic toxicity and efficacy of tacrolimus in rats

“…Pharmacokinetic studies have shown that the steady-state daily exposure tacrolimus with the once-daily formulation is equivalent to that with the standard formulation. Furthermore, the new formulation is associated with a lower Cmax (Heffron et al, 2007). Although the side effects of tacrolimus.…”

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“…Furthermore, clinical trials in transplant recipients that substituted one formulation for the other but retained the same total daily dose demonstrated equivalent exposure and similar ratios of C min to AUC0-24 for twice-daily and once-daily tacrolimus. [16][17][18] Therefore, the decision was made to apply the same therapeutic drug monitoring strategy (measurement of C min ) and target concentration range to stable organ transplant recipients irrespective of the formulation used in clinical practice. However, the information required to guide the appropriate tacrolimus dose in de novo LDLT recipients is currently lacking.…”