Sustained inhibition of calcineurin activity with a Melt-Dose Once-daily Tacrolimus formulation in renal transplant recipients.

Tacrolimus (Tac) is the cornerstone calcineurin inhibitor in transplantation. Extended-release Meltdose formulation (Tac-LCP) offers better bioavailability compared to immediate-release formulation (Tac-IR). We postulated that the less fluctuating pharmacokinetic profile of Tac-LCP might maintain a sustained inhibition of calcineurin activity (CNA) between dose intervals. Higher concentrations (Cmax ) after Tac-IR may not result in a more potent CNA inhibition due to a capacity-limited effect. This study was aimed at evaluating the pharmacodynamic/pharmacokinetic profiles of Tac-IR compared with Tac-LCP. An open-label, prospective, non-randomized, investigator-driven study was conducted. Twenty-five kidney transplant recipients receiving Tac-IR were switched to Tac-LCP. Before and 28 days after conversion, intensive CNA-pharmacodynamic and pharmacokinetic sampling were conducted using UHPLC-MS/MS. Pharmacodynamic non-linear mixed effects model was performed in Phoenix-WinNonlin. Statistically significant higher Cmax (p<0.001) after Tac-IR did not result in lower CNA as compared to after Tac-LCP (p=0.860). Tac-LCP showed a statistically more maintained CNA inhibition between dose intervals (AUE0-24h ) compared to Tac-IR, in which CNA returned to pre-dose levels after 4 hours of drug intake (373.8 vs 290.5 pmol RII· h/min·mg prot, Tac-LCP vs Tac-IR; p=0.039). No correlation was achieved between any pharmacodynamic and pharmacokinetic parameters in any formulations. Moreover, Tac concentration to elicit a 50 % of the maximum response (IC50 ) was 9.24 ng/mL. The higher Cmax after Tac-IR does not result in an additional CNA inhibition compared to Tac-LCP attributable to a capacity-limited effect. Tac-LCP may represent an improvement of the pharmacodynamic of Tac due to the more sustained CNA inhibition during dose intervals.