The calcineurin activity profiles of cyclosporin and tacrolimus are different in stable renal transplant patients

Abstract

Summary Cyclosporin and tacrolimus remain the cornerstone immunosuppressive drugs in organ transplantation. Dosing and monitoring these drugs is based on pharmacokinetic protocols, but measuring a pharmacodynamic parameter, calcineurin phosphatase (CaN) activity, could be a valuable supplement in determining optimal doses. Forty stable renal transplant patients were investigated three times in a 6‐month period. Blood samples were drawn at 0, 1, 2, 3 and 4 h after oral intake of tacrolimus (FK) or cyclosporin at days 1 and 180. At day 90, one blood sample at trough level (FK) or C2 level (cyclosporin A, CsA) was drawn. CaN activity was determined in whole blood as the release of 32P from a phosphorylated peptide. Activity of the 32P was quantitated by liquid scintillation and results converted to Units CaN, utilizing a calibration curve with CaN. We demonstrated that calcineurin activity profiles at days 1 and 180 were the same for both drugs. Furthermore, we found that patients treated with tacrolimus or cyclosporin displayed different calcineurin activity profiles. We found that cyclosporin displayed greater calcineurin inhibition than tacrolimus. We have demonstrated that the two drugs exert significantly different effects on calcineurin activity in renal transplant patients with stable, well‐functioning grafts and that tacrolimus‐treated patients can maintain good, stable graft function with minimal CaN inhibition.

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

“…2,7,13,34 As previously described by other authors, our results showed that Tac-IR-treated patients reached significant reduction of CNA in the first hours after drug intake (1-3 hours) and a recovery to baseline levels after 4 hours. 17,[35][36][37] This rapid recovery could be clinically relevant, especially in nonadherent recipients in which the evening drug intake was delayed. In this context, a prolonged under-immunosuppression during that interval could promote the activation of alloreactive T-cells and, ultimately, contribute partly to graft rejection.…”

Early conversion from cyclosporine to tacrolimus increases renal graft function in chronic allograft nephropathy at BANFF stages I and II

“…[25] found a greater calcineurin inhibition of cyclosporine than of tacrolimus using phosphorylated peptides and liquid scintillation. In his study including patients with well‐functioning grafts, a minimal calcineurin phosphatase activity in tacrolimus‐treated patients was sufficient to maintain a stable graft function [25]. To see if these significantly different calcineurin activity profiles have an impact on graft function, we monitored inulin and PAH clearances of a subgroup of groups A and B for 3 months.…”

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).…”