Montero Pérez, NúriaFontova, PereColom Codina, HelenaRigo Bonnin, RaúlBestard Matamoros, OriolVidal Alabró, Annavan Merendonk, LisanneCerezo, GemaPolo, CarolinaMelilli, EdoardoManonelles, AnnaMeneghini, MariaColoma, AnaCruzado, Josep Ma.Torras Ambròs, JoanGrinyó Boira, Josep M.Lloberas Blanch, Núria2024-02-272024-02-272021-02-240009-9236https://hdl.handle.net/2445/208137Tacrolimus (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.43 p.application/pdfeng(c) American Society for Clinical Pharmacology and Therapeutics, 2021ImmunosupressorsTrasplantament renalCromatografiaImmunosupressive agentsKidney transplantationChromatographyinfo:eu-repo/semantics/article7114222024-02-27info:eu-repo/semantics/openAccess33626199