Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Plusultra pharma GmbH, Fritz-Vomfelde-Str. 36, 40547 Düsseldorf, Germany
Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants
ATC code: Not yet assigned
The exact mechanism of action of sirolimus in the treatment of angiofibroma in the tuberous sclerosis complex is not exactly known.
In general, sirolimus inhibits activation of mTOR which is a serine/threonine protein kinase that belongs to the phosphatidylinositol-3-kinase (PI3K)-related kinase family and regulates cellular metabolism, growth and proliferation. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. This complex binds to and inhibits the activation of mTOR.
Sirolimus gel was evaluated in a Phase III, randomised, double-blind, placebo-controlled study (NPC12G-1).
In this study, patients enrolled were aged ≥6 years with a diagnosis of tuberous sclerosis complex with ≥ 3 facial, red angiofibroma (AF) lesions ≥2 mm in diameter, and who had not received prior laser therapy or surgery. Patients with clinical findings such as erosion, ulcer and eruption on or around the lesion of angiofibroma, which may affect assessment of safety or efficacy, were excluded.
Sirolimus gel (or matching placebo) was applied to facial AF lesions twice daily for 12 weeks, with a Hyftor gel amount of 125 mg (corresponding to 0.25 mg sirolimus) per 50 cm² affected skin area. No other medicinal products with an anticipated treatment effect on AF associated with tuberous sclerosis complex were allowed.
A total of 62 patients were enrolled (30 in the sirolimus gel group and 32 in the placebo group). The mean age was 21.6 years in the sirolimus gel group and 23.3 years in the placebo group and paediatric patients accounted for 44% overall trial population.
The results of the study showed a statistically significant increase in composite AF improvement (defined as concomitant improvement in AF size and AF redness) at 12 weeks with sirolimus gel treatment, compared with placebo treatment, based on independent review committee (IRC) assessment. The responder rate, defined as patients with improvement or markedly improvement, was 60% with sirolimus gel versus 0% with placebo (see Table 2).
Table 2. Efficacy results in study NPC-12G-1: composite AF improvement by IRC at week 12:
| Sirolimus gel | Placebo | |
|---|---|---|
| Patients, n (%) | 30 (100.0) | 32 (100.0) |
| Markedly improved | 5 (16.7) | 0 |
| Improved | 13 (43.3) | 0 |
| Slightly improved | 11 (36.7) | 5 (15.6) |
| Unchanged | 1 (3.3) | 26 (81.3) |
| Slightly exacerbated | 0 | 0 |
| Exacerbated | 0 | 0 |
| Not evaluated | 0 | 1 (3.1) |
| p-value (Wilcoxon rank sum test) | <0.001 | |
Change in AF size at Week 12 compared to baseline was markedly improved or improved in 60% (95% Confidence Interval (CI): 41%-77%) of patients receiving sirolimus gel vs 3% (95% CI: 0%-11%) of patients receiving placebo. Change in AF redness at Week 12 compared to baseline (by IRC) was markedly improved or improved in 40% (95% CI: 23%-59%) of patients receiving sirolimus gel vs 0% (95% CI: 0%-11%) of patients receiving placebo. Table 3 summarises efficacy in different age groups.
Table 3. Efficacy results in study NPC-12G-1: composite AF improvement by IRC at week 12, stratified by age. Data presented indicated the outcome “markedly improved” and "improved":
| Sirolimus gel | Placebo | p-value* | |
|---|---|---|---|
| 6-11 years | 5/6 (83.3%) | 0/6 (0.0%) | 0.004 |
| 12-17 years | 6/7 (85.7%) | 0/6 (0.0%) | 0.010 |
| ≥18 years | 7/17 (41.2%) | 0/20 (0.0%) | 0.000 |
* Wilcoxon 2-sample test
In the phase III study in patients treated for angiofibroma, 70% of patients had measurable sirolimus plasma concentrations after 12 weeks of treatment (range 0.11-0.50 ng/ml). Blood samples were obtained in the 52-week long-term-study at pre-defined time points and the maximum sirolimus concentration measured at any time in adult patients was 3.27 ng/ml and the maximum sirolimus concentration measured at any time in paediatric patients was 1.80 ng/ml.
For systemically administered sirolimus, terminal half-life in stable renal transplant patients after multiple oral doses was 62±16 hours.
The blood to plasma ratio of 36 indicates that sirolimus is extensively partitioned into formed blood elements.
Sirolimus is a substrate for both, cytochrome CYP3A4 and P-gp. Sirolimus is extensively metabolised by O-demethylation and/or hydroxylation. Seven major metabolites, including hydroxyl, demethyl, and hydroxydemethyl, are identifiable in whole blood. Sirolimus is the major component in human whole blood and contributes to greater than 90% of the immunosuppressive activity.
Excretion of sirolimus is mainly via the hepatic/faecal route. After a single oral dose of [14C]-sirolimus in healthy volunteers, the greatest amount (91.1%) of radioactivity was recovered from the faeces, and only a minor amount (2.2%) was excreted in urine.
There are no pharmacokinetic data available after administration of sirolimus gel to patients aged 65 years and older since studies performed with sirolimus gel did not include patients of this age (see sections 4.2).
Pharmacokinetic data from patients with renal impairment are not available.
Pharmacokinetic data from patients with hepatic impairment are not available.
Descriptive statistics of sirolimus blood concentrations revealed no relevant differences in post-dose samples taken after 4 and 12 weeks of treatment between adult and paediatric patients aged 6-11 years and 12-17 years.
In cynomolgus monkeys treated twice daily with 2 mg/g and 8 mg/g sirolimus gel for 9 months toxic effects were observed in one male at 8 mg/g gel and one female at 2 mg/g gel at exposure levels similar to clinical exposure levels following systemic administration of sirolimus and with possible relevance to clinical use, were as follows: typhlitis, colitis, and rectitis, vacuolation of the renal proximal tubular epithelium, dilation of distal tubule and collecting ducts, enlargement of the adrenal glands and hypertrophy/eosinophilia of the zona fasciculata, hypocellularity of the bone marrow, atrophy of thymus, lymph nodes and white pulp of the spleen, acinar atrophy of the exocrine pancreas and submandibular gland.
Following systemic treatment with sirolimus, pancreatic islet cell vacuolation, testicular tubular degeneration, gastrointestinal ulceration, bone fractures and calluses, hepatic haematopoiesis, and pulmonary phospholipidosis were observed.
Photosensitivity-like reactions were observed in local tolerance studies in guinea pigs.
Sirolimus was not mutagenic in the in vitro bacterial reverse mutation assays, the Chinese hamster ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay.
Long-term carcinogenicity studies conducted in mouse and rat using systemic administration of sirolimus showed increased incidences of lymphomas (male and female mouse), hepatocellular adenoma and carcinoma (male mouse) and granulocytic leukaemia (female mouse). In mouse, chronic ulcerative skin lesions were increased. The changes may be related to chronic immunosuppression. In rat, testicular interstitial cell adenomas were noted.
A two-stage skin carcinogenesis bioassay in mice showed no development of skin masses following treatment with 2 mg/g or 8 mg/g sirolimus gel indicating that sirolimus gel does not promote skin carcinogenesis when administered after initiation with dimethylbenz[a]anthracene (DMBA).
In reproduction toxicity studies using systemic administration of sirolimus, decreased fertility in male rats was observed. Partly reversible reductions in sperm counts were reported in a 13-week rat study. Reductions in testicular weights and/or histological lesions (e.g. tubular atrophy and tubular giant cells) were observed in rats and in a monkey study. In rats, sirolimus caused embryo/foetotoxicity that was manifested as mortality and reduced foetal weights (with associated delays in skeletal ossification).
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