Improved Kidney Allograft Function after Early Conversion of Fast IR-Tac Metabolizers to LCP-Tac

Abstract

Fast tacrolimus (Tac) metabolism is associated with a more rapid decline of renal function after renal transplantation (RTx). Because the pharmacokinetics of LCP-Tac (LCPT) and immediate-release Tac (IR-Tac) differ, we hypothesized that switching from IR-Tac to LCPT in kidney transplant recipients would improve the estimated glomerular filtration rate (eGFR), particularly in fast metabolizers. For proof of concept, we performed a pilot study including RTx patients who received de novo immunosuppression with IR-Tac. A Tac concentration-to-dose ratio (C/D ratio) < 1.05 ng/mL·1/mg defined fast metabolizers and ≥1.05 ng/mL·1/mg slow metabolizers one month after RTx. Patients were switched to LCPT ≥ 1 month after transplantation and followed for 3 years. Fast metabolizers (n = 58) were switched to LCPT earlier than slow metabolizers (n = 22) after RTx (2.0 (1.0–253.1) vs. 13.2 (1.2–172.8) months, p = 0.005). Twelve months after the conversion to LCPT, Tac doses were reduced by about 65% in both groups. The C/D ratios at 12 months had increased from 0.66 (0.24–2.10) to 1.74 (0.42–5.43) in fast and from 1.15 (0.32–3.60) to 2.75 (1.08–5.90) in slow metabolizers. Fast metabolizers showed noticeable recovery of mean eGFR already one month after the conversion (48.5 ± 17.6 vs. 41.5 ± 17.0 mL/min/1.73 m², p = 0.032) and at all subsequent time points, whereas the eGFR in slow metabolizers remained stable. Switching to LCPT increased Tac bioavailability, C/D ratio, and was associated with a noticeable recovery of renal function in fast metabolizers. Conversion to LCPT is safe and beneficial early after RTx.

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

“…We can make the hypothesis that the improvement of tremors and neurologic symptoms after switch to LCPT can be explained by the C 0 /D ratio improvement. Previous studies have already shown that switching to LCPT increased tacrolimus bioavailability, C/D ratio, and was associated with a noticeable recovery of renal function in fast metabolizers [22]. These results are consistent with previous reports using the MeltDose ® technology, which demonstrated an increased bioavailability of LCPT compared with twice-daily formulations of tacrolimus [12,14,16] and with PR-TAC [30].…”

“…We can make the hypothesis that the improvement of tremors and neurologic symptoms after switch to LCPT can be explained by the C 0 /D ratio improvement. Previous studies have already shown that switching to LCPT increased tacrolimus bioavailability, C/D ratio, and was associated with a noticeable recovery of renal function in fast metabolizers [ 22 ].…”

“…This is consistent with evidence from liver or kidney transplant patients, which indicates that LCPT had less adverse impact on kidney function than the twice-daily tacrolimus formulation [ 13 ]. Switching to LCPT increased the bioavailability of tacrolimus and concentration-to-dose ratio, and was associated with a noticeable recovery of renal function in fast metabolizers [ 22 ]. It has been suggested that this reduced kidney toxicity may be due to a reduced peak tacrolimus concentration, in addition to improved bioavailability and reduced trough blood concentrations, after conversion to LCPT [ 13 ].…”

“…In addition, LCPT has been shown to be at least as effective as IR-TAC in stable kidney transplant patients [16,17], or as IR-TAC and PR-TAC in newly transplanted patients [18,19], as measured by treatment failure rates at 6 and 12 months. The pre-dose concentration to daily dose (C 0 /D) ratio of tacrolimus seems to be an appropriate tool for identifying patients at risk of developing calcineurin-inhibitor toxicity such as rejection and lower renal function with increased risk of poor outcome after kidney transplantation [20][21][22]. A low tacrolimus concentration/ dose ratio has been shown to increase the risk for the development of acute calcineurin inhibitor-induced nephrotoxicity [23].…”

Tacrolimus—why pharmacokinetics matter in the clinic

“…Since the tremor and also the nephrotoxicity of Tac is related with a certain degree to Cmax, LCP-Tac (with lower Cmax) might be beneficial in susceptible patients, especially rapid metabolizers ( 87 , 144 ). Using retrospective data, we observed that switching to LCP-Tac was associated with a noticeable recovery of renal function in fast metabolizers ( 145 ). In liver transplant recipients, improvement in renal function was observed 12 months after conversion from standard-release Tac (IR- or ER-Tac) to LCP-Tac ( 146 ).…”