Impact of Switching From Immediate- or Prolonged-Release to Once-Daily Extended-Release Tacrolimus (LCPT) on Tremor in Stable Kidney Transplant Recipients: The Observational ELIT Study

Abstract

Once-daily extended-release tacrolimus (LCPT) exhibits increased bioavailability versus immediate-release (IR-TAC) and prolonged release (PR-TAC) tacrolimus. Improvements in tremor were previously reported in a limited number of kidney transplant patients who switched to LCPT. We conducted a non-interventional, non-randomized, uncontrolled, longitudinal, prospective, multicenter study to assess the impact of switching to LCPT on tremor and quality of life (QoL) in a larger population of stable kidney transplant patients. The primary endpoint was change in The Essential Tremor Rating Assessment Scale (TETRAS) score; secondary endpoints included 12-item Short Form Survey (SF-12) scores, tacrolimus trough concentrations, neurologic symptoms, and safety assessments. Subgroup analyses were conducted to assess change in TETRAS score and tacrolimus trough concentration/dose (C₀/D) ratio by prior tacrolimus formulation and tacrolimus metabolizer status. Among 221 patients, the mean decrease of TETRAS score after switch to LCPT was statistically significant (p < 0.0001 vs. baseline). There was no statistically significant difference in change in TETRAS score after switch to LCPT between patients who had received IR-TAC and those who had received PR-TAC before switch, or between fast and slow metabolizers of tacrolimus. The overall increase of C₀/D ratio post-switch to LCPT was statistically significant (p < 0.0001) and from baseline to either M1 or M3 (both p < 0.0001) in the mITT population and in all subgroups. In the fast metabolizers group, the C₀/D ratio crossed over the threshold of 1.05 ng/mL/mg after the switch to LCPT. Other neurologic symptoms tended to improve, and the SF-12 mental component summary score improved significantly. No new safety concerns were evident. In this observational study, all patients had a significant improvement of tremor, QoL and C₀/D ratio post-switch to LCPT irrespective of the previous tacrolimus formulation administered (IR-TAC or PR-TAC) and irrespective from their metabolism status (fast or slow metabolizers).

Keywords: C0/D ratio; LCPT; extended-release tacrolimus; fast metabolizer; immunosuppression; kidney transplantation; quality of life; tremor.

FIGURE 1

Population flow chart. *Three patients were excluded from the primary endpoint analyses (one patient had no evaluable TETRAS data on Day 0, and two patients had no post-baseline TETRAS data); therefore, the primary endpoint analysis was performed using data from 221 patients. mITT, modified intent-to-treat; TETRAS, The Essential Tremor Rating Assessment Scale.

FIGURE 2

Tremor evaluation using the TETRAS score after switching to LCPT in the modified intent-to-treat (mITT) population: (A) IR-TAC pretreated patients versus PR-TAC pretreated patients, and (B) fast metabolizer patients versus slow metabolizer patients. CI, confidence interval; D, day; IR-TAC, immediate-release tacrolimus; M, month; NS, not significant; PR-TAC, prolonged-release tacrolimus; TETRAS, The Essential Tremor Rating Assessment Scale.

FIGURE 3

Trough concentration/dose (C₀/D) ratio after switching to LCPT in the modified intent-to-treat (mITT) population: (A) IR-TAC pretreated patients versus PR-TAC pretreated patients; and (B) fast metabolizer patients versus slow metabolizer patients. CI, confidence interval; D, day; IR-TAC, immediate-release tacrolimus; M, month; NS, not significant; PR-TAC, prolonged-release tacrolimus.

FIGURE 4

Mean 12-item Short Form Survey (SF-12) scores from baseline to Month 3 (M3) in the modified intent-to-treat population. D0, Day 0 (baseline); QoL, quality of life.