l, the effects of tacrolimus appear to be mediated by binding to a cytosolic protein (FKBP12) which is responsible for the intracellular accumulation of the compound. The FKBP12-tacrolimus complex specifically and competitively binds to and inhibits calcineurin, leading to a calcium-dependent inhibition of T-cell signal transduction pathways, thereby preventing transcription of a discrete set of cytokine genes.
Pharmacodynamic effect
Tacrolimus is a highly potent immunosuppressive agent and has proven activity in both in vitro and in vivo experiments.
In partiular, tacrolimus inhibits the formation of cytotoxic lymphocytes, which are mainly responsible for graft rejection. Tacrolimus suppresses T-cell activation and T-helper-cell dependent B-cell proliferation, as well as the formation of lymphokines (such as interleukins-2, -3, and γ-interferon) and the expression of the interleukin-2 receptor.
Clinical efficacy and safety
Results from clinical trials performed with once-daily tacrolimus, Envarsus
Kidney transplantation
The efficacy and safety of Envarsus and Prograf, both in combination with Mycophenolate Mofetil (MMF) corticosteroids, and IL-2 receptor antagonist as per the standard of care was compared in a randomised, double-blind, double-dummy study, in 543 de novo kidney transplant recipients.
The percentage of patients with one or greater than one episodes of clinically-suspected and treated rejections during the 360-day study was 13.8% for the Envarsus group(N=268) and 15.6% for the Prograf group (N=275). The event rate for centrally-read, biopsy-confirmed acute rejection (BPAR) during the 360-day study was 13.1% in the Envarsus group (N=268) and 13.5% in the Prograf group (N=275). The efficacy failure rate as measured by the composite endpoint of death, graft loss, centrally read BPAR and loss to follow-up was 18.3% in the Envarsus group and 19.6% in the Prograf group. The treatment difference (Envarsus-Prograf) was -1.35% (95% confidence interval [-7.94%,5.27%]). Treatment-emergent fatal adverse events occurred in 1.8% of Envarsus patients and 2.5% of Prograf patients.
The efficacy and safety of Envarsus and Prograf, both in combination with mycophenolate mofetil (MMF) or mycophenolate sodium (MPS) and corticosteroids, was compared in 324 stable kidney transplant recipients. The event rate for locally read biopsy-confirmed acute rejection (BPAR) during the 360 day study was 1.2% in the Envarsus group (N=162) post conversion from Prograf at a dose ratio of 1: 0.7 (mg:mg) and 1.2% in the group maintained on Prograf (N=162). The efficacy failure rate as measured by the composite endpoint of death, graft loss, locally read BPAR and loss to follow-up was 2.5% in both the Envarsus and Prograf groups. The treatment difference (Envarsus - Prograf) was 0% (95% confidence interval [-4.21%, 4.21%]). The treatment failure rate using the same composite end-point with centrally read BPAR was 1.9% in the Envarsus group and 3.7% in the Prograf group (95% confidence interval [-6.51%, 2.31%]). Treatment emergent fatal adverse events occurred in 1.2% of Envarsus patients and 0.6% of Prograf patients.
Liver transplantation
The pharmacokinetics, efficacy and safety of Envarsus and tacrolimus immediate-release capsules , both in combination with corticosteroids was compared in 117 liver transplant recipients, of whom 88 received treatment with Envarsus. In the de novo liver transplant study, 29 subjects were t |
