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Sustained inhibition of calcineurin activity with a Melt‐Dose Once‐daily Tacrolimus formulation in renal transplant recipients
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Tacrolimus (Tac) is the cornerstone calcineurin inhibitor in transplantation. Extended-release Meltdose formulation (Tac-LCP) offers better bioavailability compared with immediate-release formulation (Tac-IR). We postulated that the less fluctuating pharmacokinetic (PK) profile of Tac-LCP might maintain a sustained inhibition of calcineurin activity (CNA) between dose intervals. Higher concentrations (peak plasma concentration (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 (PD)/PK profiles of Tac-IR compared with Tac-LCP. An open-label, prospective, nonrandomized, 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-PD and PK sampling were conducted using ultra-high-performance liquid chromatography-tandem accurate mass spectrometry. PD nonlinear 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 with after Tac-LCP (P = 0.860). Tac-LCP showed a statistically more maintained CNA inhibition between dose intervals (area under the effect-time curve from 0 to 24 hours (AUE0-24h )) compared with Tac-IR, in which CNA returned to predose 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 PD and PK parameters in any formulations. Moreover, Tac concentration to elicit a 50% of the maximum response (half-maximal inhibitory concentration) was 9.24 ng/mL. The higher Cmax after Tac-IR does not result in an additional CNA inhibition compared with Tac-LCP attributable to a capacity-limited effect. Tac-LCP may represent an improvement of the PD of Tac due to the more sustained CNA inhibition during dose intervals.
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MONTERO PÉREZ, Núria, FONTOVA, Pere, COLOM CODINA, Helena, RIGO BONNIN, Raúl, BESTARD MATAMOROS, Oriol, VIDAL ALABRÓ, Anna, VAN MERENDONK, Lisanne, CEREZO, Gema, POLO, Carolina, MELILLI, Edoardo, MANONELLES, Anna, MENEGHINI, Maria, COLOMA, Ana, CRUZADO, Josep ma., TORRAS AMBRÒS, Joan, GRINYÓ BOIRA, Josep m., LLOBERAS BLANCH, Núria. Sustained inhibition of calcineurin activity with a Melt‐Dose Once‐daily Tacrolimus formulation in renal transplant recipients. _Clinical Pharmacology & Therapeutics_. 2021. Vol. 110, núm. 1, pàgs. 238-247. [consulta: 24 de gener de 2026]. ISSN: 0009-9236. [Disponible a: https://hdl.handle.net/2445/208137]