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.
Highlights
During the last decades, tacrolimus (Tac) has become the most commonly prescribed calcineurin inhibitor (CNI) after solid organ transplantation [1,2]
We followed up 80 renal dose ratio (RTx) recipients who started on Immediate-release Tac (IR-Tac) and were switched to LCPT one month after RTx or later
We found that fast Tac metabolism in IR-treated RTx patients is associated with higher Tac peak levels and higher rejection and BKVN rates, leading to worse renal function compared with IR-treated slow metabolizers [5,6,11,13]
Summary
Tacrolimus (Tac) has become the most commonly prescribed calcineurin inhibitor (CNI) after solid organ transplantation [1,2]. Immediate-release Tac (IR-Tac) was the first formulation on the market and has to be administered twice-daily, resulting in two blood peak levels: a higher one in the morning, about 1.5 to 2 h after drug intake, and a lower one about 12 h later [3]. Extended-release Tac (ER-Tac) was developed to simplify administration by replacing croscarmellose in IR-Tac with ethylcellulose in ER-Tac. The formulation of ER-Tac allows for once-daily administration, resulting in higher adherence rates [4], but is associated with an early high Tac peak level after ingestion that is comparable to the first peak of IR-Tac [3]. LCP-Tac (LCPT) is a new formulation using the MeldDose® prolonged-release technology that provides absorption throughout the entire gastrointestinal tract. This results in lower and later peak concentrations approximately 4 to 6 h after drug intake [3]
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