A single‐center, open‐label, randomized cross‐over study to evaluate the pharmacokinetics and bioavailability of once‐daily prolonged‐release formulations of tacrolimus in de novo liver transplant recipients

Abstract

Background: The narrow therapeutic window of tacrolimus (Tac) requires intense drug monitoring to achieve adequate efficacy while minimizing dose-related toxicities. Once-daily formulations of Tac (LCP-Tac and PR-Tac) have been recently designed for higher bioavailability and a more consistent exposure over time, as opposed to the twice-daily, administered immediate-release formulation of Tac (IR-Tac). Methods: This single-center, open-label, randomized cross-over pharmacokinetic (PK) study compares extended-release LCP-Tac with the prolonged-release formulation of tacrolimus (PR-Tac) in adult de novo liver transplant recipients.Eligible patients were screened and randomized 1:1 to the two treatment arms up to 30 days after liver transplantation. Patients were administered either LCP-Tac or PR-Tac for 14 days followed by another 14-day time interval of the other once-daily Tac medication. A 24hr-PK profile was obtained at the end of each time interval.Results: Nine patients (45%) completed the study resulting in a total of 18 Tac PK profiles. Overall, the profile of the mean concentrations indicated a flattened kinetic of LCP-Tac compared to PR-Tac, especially in the first 3 h after drug intake. The average cumulative dose per day to achieve equivalent trough levels was approximately 25% lower for LCP-Tac (8.7 mg) than for PR-Tac (11.7 mg). LCP-Tac resulted in a longer t max and fewer peak-to-trough fluctuations compared to PR-Tac. Conclusion: Despite methodological weaknesses that limit the conclusions, we have found a more consistent drug exposure for LCP-Tac in de novo LT recipients. LCP-Tac demonstrated a greater bioavailability compared to PR-Tac.

Effectiveness and safety of once‐daily tacrolimus formulations in de novo liver transplant recipients: The PRETHI study

“…In a phase II study assessing the early post‐transplant period in de novo liver transplant patients, LCPT and IR‐Tac showed similar efficacy and safety 18 . However, studies comparing the effectiveness and safety of once‐daily formulations in de novo liver transplantation are limited to a retrospective study including 35 patients followed for 30 post‐transplant days 19 and a single‐center study comparing the pharmacokinetics and bioavailability of both formulations 20 . Data comparing the effectiveness of once‐daily tacrolimus formulations in de novo patients in other transplant organs are also scarce and limited to kidney transplant recipients.…”