Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Sandoz Limited, Park View, Riverside Way, Watchmoor Park, Camberley, Surrey, GU15 3YL, United Kingdom
Pharmacotherapeutic group: Immunosuppressants, calcineurin inhibitors
ATC code: L04AD02
At the molecular level, 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.
Tacrolimus is a highly potent immunosuppressive agent and has proven activity in both in vitro and in vivo experiments.
In particular, 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.
The efficacy and safety of tacrolimus prolonged-release and tacrolimus immediate-release, both in combination with corticosteroids, was compared in 471 de novo liver transplant recipients. The event rate of biopsy confirmed acute rejection within the first 24 weeks after transplantation was 32.6% in the tacrolimus prolonged-release group (N=237) and 29.3% in the tacrolimus immediate-release group (N=234). The treatment difference (prolonged-release – immediate-release) was 3.3% (95% confidence interval [-5.7%, 12.3%]).The 12-month patient survival rates were 89.2% for tacrolimus prolonged-release and 90.8% for tacrolimus immediate-release; in the tacrolimus prolonged-release arm 25 patients died (14 female, 11 male) and in the tacrolimus immediate-release arm 24 patients died (5 female, 19 male). 12-month graft survival was 85.3% for tacrolimus prolonged-release and 85.6% for tacrolimus immediate-release.
The efficacy and safety of tacrolimus prolonged-release and tacrolimus immediate-release, both in combination with mycophenolate mofetil (MMF) and corticosteroids, was compared in 667 de novo kidney transplant recipients. The event rate for biopsy-confirmed acute rejection within the first 24 weeks after transplantation was 18.6% in the tacrolimus prolonged-release group (N=331) and 14.9% in the tacrolimus immediate-release group (N=336). The treatment difference (prolonged-release – immediate-release) was 3.8% (95% confidence interval [-2.1%, 9.6%]). The 12-month patient survival rates were 96.9% for tacrolimus prolonged-release and 97.5% for tacrolimus immediate-release; in the tacrolimus prolonged-release arm 10 patients died (3 female, 7 male) and in the tacrolimus immediate-release arm 8 patients died (3 female, 5 male). 12-month graft survival was 91.5% for tacrolimus prolonged-release and 92.8% for tacrolimus immediate-release.
The efficacy and safety of tacrolimus immediate-release, ciclosporin and tacrolimus prolonged-release, all in combination with basiliximab antibody induction, MMF and corticosteroids, was compared in 638 de novo kidney transplant recipients. The incidence of efficacy failure at 12 months (defined as death, graft loss, biopsy-confirmed acute rejection, or lost to follow-up) was 14.0% in the tacrolimus prolonged-release group (N=214), 15.1% in the tacrolimus immediate-release group (N=212) and 17.0% in the ciclosporin group (N=212). The treatment difference was -3.0% (tacrolimus prolonged-release-ciclosporin) (95.2% confidence interval [-9.9%, 4.0%]) for tacrolimus prolonged-release vs. ciclosporin and -1.9% (tacrolimus immediate-release-ciclosporin) (95.2% confidence interval [-8.9%, 5.2%]) for tacrolimus immediate-release vs. ciclosporin. The 12-month patient survival rates were 98.6% for tacrolimus prolonged-release, 95.7% for tacrolimus immediate-release and 97.6% for ciclosporin; in the tacrolimus prolonged-release arm 3 patients died (all male), in the tacrolimus immediate-release arm 10 patients died (3 female, 7 male) and in the ciclosporin arm 6 patients died (3 female, 3 male). 12-month graft survival was 96.7% for tacrolimus prolonged-release, 92.9% for tacrolimus immediate-release and 95.7% for ciclosporin.
In prospective studies tacrolimus immediate-release were investigated as primary immunosuppressant in approximately 175 patients following lung, 475 patients following pancreas and 630 patients following intestinal transplantation. Overall, the safety profile of tacrolimus immediate-release in these published studies appeared to be similar to what was reported in the large studies, where tacrolimus immediate-release were used as primary treatment in liver, kidney and heart transplantation. Efficacy results of the largest studies in each indication are summarised below.
The interim analysis of a recent multicentre study using tacrolimus immediate-release discussed 110 patients who underwent 1:1 randomisation to either tacrolimus or ciclosporin. Tacrolimus was started as continuous intravenous infusion at a dose of 0.01 to 0.03 mg/kg/day and oral tacrolimus was administered at a dose of 0.05 to 0.3 mg/kg/day. A lower incidence of acute rejection episodes for tacrolimus- versus ciclosporin-treated patients (11.5% versus 22.6%) and a lower incidence of chronic rejection, the bronchiolitis obliterans syndrome (2.86% versus 8.57%), was reported within the first year after transplantation. The 1-year patient survival rate was 80.8% in the tacrolimus and 83% in the ciclosporin group.
Another randomised study included 66 patients on tacrolimus versus 67 patients on ciclosporin. Tacrolimus was started as continuous intravenous infusion at a dose of 0.025 mg/kg/day and oral tacrolimus was administered at a dose of 0.15 mg/kg/day with subsequent dose adjustments to target trough levels of 10 to 20 ng/ml. The 1-year patient survival was 83% in the tacrolimus and 71% in the ciclosporin group, the 2-year survival rates were 76% and 66%, respectively. Acute rejection episodes per 100 patient-days were numerically fewer in the tacrolimus (0.85 episodes) than in the ciclosporin group (1.09 episodes). Obliterative bronchiolitis developed in 21.7% of patients in the tacrolimus group compared with 38.0% of patients in the ciclosporin group (p=0.025). Significantly more ciclosporin treated patients (n=13) required a switch to tacrolimus than tacrolimus-treated patients to ciclosporin (n=2) (p=0.02) (Keenan et al., Ann Thoracic Surg 1995;60:580).
In an additional two-centre study, 26 patients were randomised to the tacrolimus versus 24 patients to the ciclosporin group. Tacrolimus was started as continuous intravenous infusion at a dose of 0.05 mg/kg/day and oral tacrolimus was administered at a dose of 0.1 to 0.3 mg/kg/day with subsequent dose adjustments to target trough levels of 12 to 15 ng/ml. The 1-year survival rates were 73.1% in the tacrolimus versus 79.2% in the ciclosporin group. Freedom from acute rejection was higher in the tacrolimus group at 6 months (57.7% versus 45.8%) and at 1 year after lung transplantation (50% versus 33.3%). The three studies demonstrated similar survival rates. The incidences of acute rejection were numerically lower with tacrolimus in all three studies and one of the studies reported a significantly lower incidence of bronchiolitis obliterans syndrome with tacrolimus.
A multicentre study using tacrolimus immediate-release included 205 patients undergoing simultaneous pancreas-kidney transplantation who were randomised to tacrolimus (n=103) or to ciclosporin (n=102). The initial oral per protocol dose of tacrolimus was 0.2 mg/kg/day with subsequent dose adjustments to target trough levels of 8 to 15 ng/ml by Day 5 and 5 to 10 ng/ml after Month 6. Pancreas survival at 1 year was significantly superior with tacrolimus: 91.3% versus 74.5% with ciclosporin (p<0.0005), whereas renal graft survival was similar in both groups. In total 34 patients switched treatment from ciclosporin to tacrolimus, whereas only 6 tacrolimus patients required alternative therapy.
Published clinical experience from a single centre on the use of tacrolimus immediate-release for primary treatment following intestinal transplantation showed that the actuarial survival rate of 155 patients (65 intestine alone, 75 liver and intestine, and 25 multivisceral) receiving tacrolimus and prednisone was 75% at 1 year, 54% at 5 years, and 42% at 10 years. In the early years the initial oral dose of tacrolimus was 0.3 mg/kg/day. Results continuously improved with increasing experience over the course of 11 years. A variety of innovations, such as techniques for early detection of Epstein-Barr (EBV) and CMV infections, bone marrow augmentation, the adjunct use of the interleukin-2 antagonist daclizumab, lower initial tacrolimus doses with target trough levels of 10 to 15 ng/ml, and most recently allograft irradiation were considered to have contributed to improved results in this indication over time.
In man tacrolimus has been shown to be able to be absorbed throughout the gastrointestinal tract. Available tacrolimus is generally rapidly absorbed. Dailiport is a prolonged-release formulation of tacrolimus resulting in an extended oral absorption profile with an average time to maximum blood concentration (Cmax) of approximately 2 hours (tmax).
Absorption is variable and the mean oral bioavailability of tacrolimus (investigated with the tacrolimus immediate-release formulation) is in the range of 20% - 25% (individual range in adult patients 6%-43%). The oral bioavailability of tacrolimus prolonged-release was reduced when it was administered after a meal. Both the rate and extent of absorption of tacrolimus prolonged-release were reduced when administered with food.
Bile flow does not influence the absorption of tacrolimus and therefore treatment with Dailiport may commence orally.
A strong correlation exists between AUC and whole blood trough levels at steady-state for tacrolimus prolonged-release. Monitoring of whole blood trough levels therefore provides a good estimate of systemic exposure.
In man, the disposition of tacrolimus after intravenous infusion may be described as biphasic.
In the systemic circulation, tacrolimus binds strongly to erythrocytes resulting in an approximate 20:1 distribution ratio of whole blood/plasma concentrations. In plasma, tacrolimus is highly bound (>98.8%) to plasma proteins, mainly to serum albumin and α-1-acid glycoprotein.
Tacrolimus is extensively distributed in the body. The steady-state volume of distribution based on plasma concentrations is approximately 1300 l (healthy subjects). Corresponding data based on whole blood averaged 47.6 l.
Tacrolimus is widely metabolised in the liver, primarily by the cytochrome P450-3A4. Tacrolimus is also considerably metabolised in the intestinal wall. There are several metabolites identified. Only one of these has been shown in vitro to have immunosuppressive activity similar to that of tacrolimus. The other metabolites have only weak or no immunosuppressive activity. In systemic circulation only one of the inactive metabolites is present at low concentrations. Therefore, metabolites do not contribute to the pharmacological activity of tacrolimus.
Tacrolimus is a low-clearance substance. In healthy subjects, the average total body clearance estimated from whole blood concentrations was 2.25 l/h. In adult liver, kidney and heart transplant patients, values of 4.1 l/h, 6.7 l/h and 3.9 l/h, respectively, have been observed. Factors such as low haematocrit and protein levels, which result in an increase in the unbound fraction of tacrolimus, or corticosteroid-induced increased metabolism, are considered to be responsible for the higher clearance rates observed following transplantation.
The half-life of tacrolimus is long and variable. In healthy subjects, the mean half-life in whole blood is approximately 43 hours.
Following intravenous and oral administration of 14C-labelled tacrolimus, most of the radioactivity was eliminated in the faeces. Approximately 2% of the radioactivity was eliminated in the urine. Less than 1% of unchanged tacrolimus was detected in the urine and faeces, indicating that tacrolimus is almost completely metabolised prior to elimination: bile being the principal route of elimination.
The kidneys and the pancreas were the primary organs affected in toxicity studies performed in rats and baboons. In rats, tacrolimus caused toxic effects to the nervous system and the eyes. Reversible cardiotoxic effects were observed in rabbits following intravenous administration of tacrolimus.
When tacrolimus is administered intravenously as rapid infusion/bolus injection at a dose of 0.1 to 1.0 mg/kg, QTc prolongation has been observed in some animal species. Peak blood concentrations achieved with these doses were above 150 ng/mL which is more than 6-fold higher than mean peak concentrations observed with tacrolimus prolonged-release in clinical transplantation.
Embryofoetal toxicity was observed in rats and rabbits and was limited to doses that caused significant toxicity in maternal animals. In rats, female reproductive function including birth was impaired at toxic doses and the offspring showed reduced birth weights, viability and growth. A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility was observed in rats.
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