Sustained Inhibition of Calcineurin Activity With a Melt‐Dose Once‐daily Tacrolimus Formulation in Renal Transplant Recipients

Abstract

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.

Pharmacodynamic Monitoring of Ciclosporin and Tacrolimus: Insights From Nuclear Factor of Activated T-Cell–Regulated Gene Expression in Healthy Volunteers

“…This is in contrast to a recent publication on tacrolimus, where higher maximum concentrations were not associated with a stronger suppression of calcineurin activity. 35 Although the reasons for this discrepancy are unclear, they might be explained by differences in the applied assays. Calcineurin activity, as used by Fontova et al is "upstream" of cellular functions, which is the basis of the “functional” assay in this study, quantifying NFAT-RGE after ex vivo stimulation.…”

Influence of the Circadian Timing System on Tacrolimus Pharmacokinetics and Pharmacodynamics After Kidney Transplantation

“…This may be explained by the transient PD profile observed after morning Tac dose characterized by a rapid return to pre-dose levels once the I nadir was reached, which differs to the more sustained inhibition after the I nadir , which was noticed following night dose. Previous studies also showed this rapid recovery of CN activity to pre-dose levels after the morning Tac dose (Koefoednielsen and Gesualdo, 2002;Koefoed-Nielsen et al, 2006;Iwasaki et al, 2018;Fontova et al, 2021). Other studies investigating lymphocyte activation have shown circadian rhythms displaying higher proinflammatory cytokine secretion during night time (Benedict et al, 2007;Fortier et al, 2011).…”

“…A post-hoc analysis of a prospective, non-randomized clinical trial was carried out at the Kidney Transplant Unit of Bellvitge University Hospital (clinicalTrials.gov NCT02961608) (Fontova et al, 2021). This clinical trial was conducted in accordance with the Declaration of Helsinki and with the local ethics committee.…”

The Effect of Intracellular Tacrolimus Exposure on Calcineurin Inhibition in Immediate- and Extended-Release Tacrolimus Formulations

“…However, acute rejection and toxicity occur even when WhB C 0 is within the therapeutic range [ 2 , 13 ]. Furthermore, results regarding correlations between WhB C 0 and AUC are variable among studies [ 2 , 14 , 15 , 16 ], possibly indicating that a single C 0 could be associated with different PK profiles. By contrast, correlation between intracellular TAC C 0 and rejection severity or lymphocyte’s activation was observed in solid organ transplant recipients [ 7 , 17 ].…”

“…Most PD studies relating TAC exposure with CN activity are based solely on WhB TAC concentrations, with differences in the study design and variables to measure drug exposure and CN activity. A poor or inexistent linear correlation between CN activity and WhB concentrations has been reported [ 15 , 20 ]. In this line, no correlation between CN activity and intracellular TAC concentrations was found in different studies [ 3 , 21 ].…”