Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: DEXCEL-PHARMA LTD, 7 Sopwith Way, Drayton Fields Industrial Estate, Daventry, Northamptonshire, NN11 8PB, United Kingdom
Pharmacotherapeutic group: Immunosuppressive agents, calcineurin inhibitors
ATC code: L04AD01
Ciclosporin (also known as ciclosporin A) is a cyclic polypeptide consisting of 11 amino acids. It is a potent immunosuppressive agent, which in animals prolongs survival of allogeneic transplants of skin, heart, kidney, pancreas, bone marrow, small intestine or lung. Studies suggest that ciclosporin inhibits the development of cell-mediated reactions, including allograft immunity, delayed cutaneous hypersensitivity, experimental allergic encephalomyelitis, Freund’s adjuvant arthritis, graft-versus-host disease (GVHD), and also T-cell dependent antibody production. At the cellular level it inhibits production and release of lymphokines including interleukin 2 (T-cell growth factor, TCGF). Ciclosporin appears to block the resting lymphocytes in the G0 or G1 phase of the cell cycle, and inhibits the antigen-triggered release of lymphokines by activated T-cells.
All available evidence suggests that ciclosporin acts specifically and reversibly on lymphocytes. Unlike cytostatic agents, it does not depress haemopoiesis and has no effect on the function of phagocytic cells.
Successful solid organ and bone marrow transplantations have been performed in man using ciclosporin to prevent and treat rejection and GVHD. Ciclosporin has been used successfully both in hepatitis C virus (HCV) positive and HCV negative liver transplants recipients. Beneficial effects of ciclosporin therapy have also been shown in a variety of conditions that are known, or may be considered to be of autoimmune origin.
Ciclosporin has been shown to be efficacious in steroid-dependent nephrotic syndrome.
The maximal blood concentration (Cmax) of ciclosporin after treatment with Deximune is achieved within 1-2 hours (Tmax). The absolute bioavailability is ~30%. The inter- and intra-individual pharmacokinetic variability is 10-20% for AUC and Cmax in healthy volunteers.
Bioequivalence studies under both fasting and fed conditions were performed to compare the pharmacokinetic parameters of Deximune and the originator product, as follows:
1. A randomised, two-way cross-over study in 24 healthy male volunteers under fasting conditions. The results of the study are presented in Table 3 below:
Table 3. Pharmacokinetic parameters – fasting conditions:
| Deximune 2x100 mg (Test) | Originator product 2x100 mg (Reference) | Test/Reference 90% CI | |
|---|---|---|---|
| (n=24) | |||
| AUCinf (ng*h*ml-1) | 4930 (1283) | 4866 (1107) | 1.01 (0.93–1.09)1 |
| Cmax (ng/ml) | 1184 (215) | 1203 (231) | 0.99 (0.90–1.09)1 |
| Tmax (h) | 1.65 (0.48) | 1.63 (0.52) | 0 (-0.25–0.25)2 |
All pharmacokinetic parameters presented are mean (SD) values
1 Geometric means of the individual ratios and 90% parametric CI
2 Median Difference and 90% non parametric CI
2. A randomised, two-way cross-over study in 39 healthy male volunteers under fed conditions. The volunteers were fed with a standard high-fat high-calorie breakfast before administration of ciclosporin. The results of the study are presented in Table 4 below:
Table 4. Pharmacokinetic parameters – fed conditions:
| Deximune 2x100 mg (Test) | Originator product 2x100 mg (Reference) | Test/Reference 90% CI | |
|---|---|---|---|
| (n=39) | |||
| AUCinf (ng*h*ml-1) | 4323 (883) | 4098 (934) | 1.06 (1.03–1.10)1 |
| Cmax (ng/ml) | 1076 (294) | 958 (311) | 1.13 (1.05–1.22)1 |
| Tmax (h) | 1.68 (0.65) | 1.75 (0.71) | 0.00 (-0.25; 0.13)2 |
All pharmacokinetic parameters presented are mean (SD) values
1 Geometric means of the individual ratios and 90% parametric CI
2 Median Difference and 90% non parametric CI
3. A randomised, two-way cross-over, food effect study in which 16 healthy male volunteers received a standard high-fat high-calorie breakfast before administration of ciclosporin.
The results of the study are presented in Table 5 below:
Table 5. Pharmacokinetic parameters – fasting versus fed conditions:
| Deximune 2x100 mg Fed conditions (Test Fed) | Deximune 2x100 mg Fasting conditions (Test Fasting) | Test Fed/Test Fasting 90% CI | |
|---|---|---|---|
| (n=16) | |||
| AUCinf (ng*h*ml-1) | 4992 (1237) | 5359 (1073) | 0.93 (0.86; 1.01)1 |
| Cmax (ng/ml) | 1109 (191) | 1308 (299) | 0.85 (0.76; 0.96)1 |
| Tmax (h) | 1.81 (0.63) | 1.31 (0.31) | 0.50 (0.25; 0.75)2 |
All pharmacokinetic parameters presented are mean (SD) values
1 Geometric means of the individual ratios and 90% parametric CI
2 Median Difference and 90% non parametric CI
The results show that food intake decreases AUC and Cmax by 7% and 15%, respectively, compared to the values obtained under fasting conditions.
The reduction in AUC and Cmax are not significant and Deximune can be administered with or without food.
Ciclosporin is distributed largely outside the blood volume with an average apparent distribution volume of 3.5 l/kg. In the blood, 33 to 47% is present in plasma, 4 to 9% in lymphocytes, 5 to 12% in granulocytes and 41 to 58% in erythrocytes. In plasma, approximately 90% is bound in proteins, mainly lipoproteins.
Ciclosporin is extensively metabolised to approximately 15 metabolites. Metabolism mainly takes place in the liver via cytochrome P450 3A4 (CYP3A4), and the main pathways of metabolism consist of mono- and dihydroxylation and N-demethylation at various positions of the molecule. All metabolites identified so far contain the intact peptide structure of the parent compound; some possess weak immunosuppressive activity (up to one-tenth that of the unchanged drug).
Elimination is primarily biliary, with only 6% of the oral dose excreted in the urine; only 0.1% is excreted in the urine as unchanged drug.
There is a high variability in the data reported on the terminal half-life of ciclosporin depending on the assay applied and the target population. The terminal half-life ranged from 6.3 hours in healthy volunteers to 20.4 hours in patients with severe liver disease (see sections 4.2 and 4.4). The elimination half-life in kidney-transplanted patients was approximately 11 hours, with a range between 4 and 25 hours.
In a study performed in patients with terminal renal failure, the systemic clearance was approximately two thirds of the mean systemic clearance in patients with normally functioning kidneys. Less than 1% of the administered dose is removed by dialysis.
An approximate 2- to 3-fold increase in ciclosporin exposure may be observed in patients with hepatic impairment. In a study performed in severe liver disease patients with biopsy-proven cirrhosis, the terminal half-life was 20.4 hours (range between 10.8 to 48.0 hours) compared to 7.4 to 11.0 hours in healthy subjects.
Pharmacokinetic data from paediatric patients given ciclosporin are very limited. In 15 renal transplant patients aged 3 -16 years, ciclosporin whole blood clearance after intravenous administration of ciclosporin was 10.6±3.7 ml/min/kg (assay: Cyclo-trac specific RIA). In a study of 7 renal transplant patients aged 2-16 years, the ciclosporin clearance ranged from 9.8 to15.5 ml/min/kg. In 9 liver transplant patients aged 0.65-6 years, clearance was 9.3±5.4 ml/min/kg (assay: HPLC). In comparison to adult transplant populations, the differences in bioavailability between intravenous ciclosporin and oral ciclosporin in paediatrics are comparable to those observed in adults.
Ciclosporin gave no evidence of mutagenic or teratogenic effects in the standard test systems with oral application (rats up to 17 mg/kg/day and rabbits up to 30 mg/kg/day orally). At toxic doses (rats at 30 mg/kg/day and rabbits at 100 mg/kg/day orally), ciclosporin was embryo- and foetotoxic as indicated by increased prenatal and postnatal mortality, and reduced foetal weight together with related skeletal retardations.
In two published research studies, rabbits exposed to ciclosporin in utero (10 mg/kg/day subcutaneously) demonstrated reduced numbers of nephrons, renal hypertrophy, systemic hypertension, and progressive renal insufficiency up to 35 weeks of age. Pregnant rats which received 12 mg/kg/day of ciclosporin intravenously (twice the recommended human intravenous dose) had foetuses with an increased incidence of ventricular septal defect. These findings have not been demonstrated in other species and their relevance for humans is unknown. No impairment in fertility was demonstrated in studies in male and female rats.
Ciclosporin was tested in a number of in vitro and in vivo tests for genotoxicity with no evidence for a clinically relevant mutagenic potential.
Carcinogenicity studies were carried out in male and female rats and mice. In the 78-week mouse study, at doses of 1, 4, and 16 mg/kg a day, evidence of a statistically significant trend was found for lymphocytic lymphomas in females, and the incidence of hepatocellular carcinomas in mid-dose males significantly exceeded the control value. In the 24-month rat study conducted at 0.5, 2 and 8 mg/kg a day, pancreatic islet cell adenomas significantly exceeded the control rate at the low dose level. The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose-related.
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