Chemical formula: C₅₃H₈₃NO₁₄ Molecular mass: 958.24 g/mol PubChem compound: 6442177
Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor. mTOR is a key serine-threonine kinase, the activity of which is known to be upregulated in a number of human cancers. Everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibits mTOR complex-1 (mTORC1) activity. Inhibition of the mTORC1 signalling pathway interferes with the translation and synthesis of proteins by reducing the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4EBP-1) that regulate proteins involved in the cell cycle, angiogenesis and glycolysis. S6K1is thought to phosphorylate the activation function domain 1 of the oestrogen receptor, which is responsible for ligand-independent receptor activation. Everolimus reduces levels of vascular endothelial growth factor (VEGF), which potentiates tumour angiogenic processes. Everolimus is a potent inhibitor of the growth and proliferation of tumour cells, endothelial cells, fibroblasts and blood-vessel-associated smooth muscle cells and has been shown to reduce glycolysis in solid tumours in vitro and in vivo.
Two primary regulators of mTORC1 signalling are the oncogene suppressors tuberin-sclerosis complexes 1 & 2 (TSC1, TSC2). Loss of either TSC1 or TSC2 leads to elevated rheb-GTP levels, a ras family GTPase, which interacts with the mTORC1 complex to cause its activation. mTORC1 activation leads to a downstream kinase signalling cascade, including activation of the S6 kinases. In TSC syndrome, inactivating mutations in the TSC1 or the TSC2 gene lead to hamartoma formation throughout the body. Besides pathological changes in brain tissue (such as cortical tubers) which may cause seizures, the mTOR pathway is also implicated in the pathogenesis of epilepsy in TSC. The mTOR regulates protein synthesis and multiple downstream cellular functions that may influence neuronal excitability and epileptogenesis. Overactivation of mTOR results in neuronal dysplasia, aberrant axonogenesis and dendrite formation, increased excitatory synaptic currents, reduced myelination, and disruption of the cortical laminar structure causing abnormalities in neuronal development and function. Preclinical studies in models of mTOR dysregulation in the brain demonstrated that treatment with an mTOR inhibitor such as everolimus could prolong survival, suppress seizures, prevent the development of new-onset seizures and prevent premature death. In summary, everolimus is highly active in this neuronal model of TSC, with benefit apparently attributable to effects on mTORC1 inhibition. However, the exact mechanism of action in the reduction of seizures associated with TSC is not fully elucidated.
In patients with advanced solid tumours, peak everolimus concentrations (Cmax) are reached at a median time of 1 hour after daily administration of 5 and 10 mg everolimus under fasting conditions or with a light fat-free snack. Cmax is dose-proportional between 5 and 10 mg. Everolimus is a substrate and moderate inhibitor of PgP.
In healthy subjects, high fat meals reduced systemic exposure to everolimus 10 mg tablets (as measured by AUC) by 22% and the peak blood concentration Cmax by 54%. Light fat meals reduced AUC by 32% and Cmax by 42%.
In healthy subjects taking a single 9 mg dose (3 × 3 mg) of everolimus dispersible tablets in suspension, high fat meals reduced AUC by 11.7% and the peak blood concentration Cmax by 59.8%. Light fat meals reduced AUC by 29.5% and Cmax by 50.2%.
Food, however, had no apparent effect on the post absorption phase concentration-time profile 24 hours post-dose of either dosage form.
The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5,000 ng/ml, is 17% to 73%. Approximately 20% of the everolimus concentration in whole blood is confined to plasma of cancer patients given everolimus 10 mg/day. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment. In patients with advanced solid tumours, Vd was 191 l for the apparent central compartment and 517 l for the apparent peripheral compartment.
Nonclinical studies in rats indicate:
There are no clinical data on the distribution of everolimus in the human brain. Non-clinical studies in rats demonstrated distribution into the brain following administration by both the intravenous and oral routes.
Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100 times less activity than everolimus itself. Hence, everolimus is considered to contribute the majority of the overall pharmacological activity.
Mean oral clearance (CL/F) of everolimus after 10 mg daily dose in patients with advanced solid tumours was 24.5 l/h. The mean elimination half-life of everolimus is approximately 30 hours.
No specific excretion studies have been undertaken in cancer patients; however, data are available from the studies in transplant patients. Following the administration of a single dose of radiolabelled everolimus in conjunction with ciclosporin, 80% of the radioactivity was recovered from the faeces, while 5% was excreted in the urine. The parent substance was not detected in urine or faeces.
After administration of everolimus in patients with advanced solid tumours, steady-state AUC0-τ was dose-proportional over the range of 5 to 10 mg daily dose. Steady-state was achieved within 2 weeks. Cmax is dose-proportional between 5 and 10 mg. tmax occurs at 1 to 2 hours post-dose. There was a significant correlation between AUC0-τ and pre-dose trough concentration at steady-state.
The safety, tolerability and pharmacokinetics of everolimus were evaluated in two single oral dose studies of everolimus tablets in 8 and 34 subjects with impaired hepatic function relative to subjects with normal hepatic function.
In the first study, the average AUC of everolimus in 8 subjects with moderate hepatic impairment (Child-Pugh B) was twice that found in 8 subjects with normal hepatic function.
In the second study of 34 subjects with different impaired hepatic function compared to normal subjects, there was a 1.6-fold, 3.3-fold and 3.6-fold increase in exposure (i.e. AUC0-inf) for subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, respectively.
Simulations of multiple dose pharmacokinetics support the dosing recommendations in subjects with hepatic impairment based on their Child-Pugh status.
Based on the results of the two studies, dose adjustment is recommended for patients with hepatic impairment.
In a population pharmacokinetic analysis of 170 patients with advanced solid tumours, no significant influence of creatinine clearance (25-178 ml/min) was detected on CL/F of everolimus. Post-transplant renal impairment (creatinine clearance range 11-107 ml/min) did not affect the pharmacokinetics of everolimus in transplant patients.
In patients with SEGA, everolimus Cmin was approximately dose-proportional within the dose range from 1.35 mg/m² to 14.4 mg/m².
In patients with SEGA, the geometric mean Cmin values normalised to mg/m² dose in patients aged <10 years and 10-18 years were lower by 54% and 40%, respectively, than those observed in adults (>18 years of age), suggesting that everolimus clearance was higher in younger patients. Limited data in patients <3 years of age (n=13) indicate that BSA-normalised clearance is about two-fold higher in patients with low BSA (BSA of 0.556 m²) than in adults. Therefore it is assumed that steady-state could be reached earlier in patients <3 years of age.
The pharmacokinetics of everolimus have not been studied in patients younger than 1 year of age. It is reported, however, that CYP3A4 activity is reduced at birth and increases during the first year of life, which could affect the clearance in this patient population.
A population pharmacokinetic analysis including 111 patients with SEGA who ranged from 1.0 to 27.4 years (including 18 patients 1 to less than 3 years of age with BSA 0.42 m² to 0.74 m²) showed that BSA-normalised clearance is in general higher in younger patients. Population pharmacokinetic model simulations showed that a starting dose of 7 mg/m² would be necessary to attain Cmin within the 5 to 15 ng/ml range in patients younger than 3 years of age. A higher starting dose of 7 mg/m² is therefore recommended for patients 1 to less than 3 years of age with SEGA.
In a population pharmacokinetic evaluation in cancer patients, no significant influence of age (27-85 years) on oral clearance of everolimus was detected.
Oral clearance (CL/F) is similar in Japanese and Caucasian cancer patients with similar liver functions. Based on analysis of population pharmacokinetics, CL/F is on average 20% higher in black transplant patients.
The preclinical safety profile of everolimus was assessed in mice, rats, minipigs, monkeys and rabbits. The major target organs were male and female reproductive systems (testicular tubular degeneration, reduced sperm content in epididymides and uterine atrophy) in several species; lungs (increased alveolar macrophages) in rats and mice; pancreas (degranulation and vacuolation of exocrine cells in monkeys and minipigs, respectively, and degeneration of islet cells in monkeys), and eyes (lenticular anterior suture line opacities) in rats only. Minor kidney changes were seen in the rat (exacerbation of age-related lipofuscin in tubular epithelium, increases in hydronephrosis) and mouse (exacerbation of background lesions). There was no indication of kidney toxicity in monkeys or minipigs.
Everolimus appeared to spontaneously exacerbate background diseases (chronic myocarditis in rats, coxsackie virus infection of plasma and heart in monkeys, coccidian infestation of the gastrointestinal tract in minipigs, skin lesions in mice and monkeys). These findings were generally observed at systemic exposure levels within the range of therapeutic exposure or above, with the exception of the findings in rats, which occurred below therapeutic exposure due to a high tissue distribution.
In a male fertility study in rats, testicular morphology was affected at 0.5 mg/kg and above, and sperm motility, sperm head count, and plasma testosterone levels were diminished at 5 mg/kg which caused a reduction in male fertility. There was evidence of reversibility.
In animal reproductive studies female fertility was not affected. However, oral doses of everolimus in female rats at ≥0.1 mg/kg (approximately 4% of the AUC0-24h in patients receiving the 10 mg daily dose) resulted in increases in pre-implantation loss.
Everolimus crossed the placenta and was toxic to the foetus. In rats, everolimus caused embryo/foetotoxicity at systemic exposure below the therapeutic level. This was manifested as mortality and reduced foetal weight. The incidence of skeletal variations and malformations (e.g. sternal cleft) was increased at 0.3 and 0.9 mg/kg. In rabbits, embryotoxicity was evident in an increase in late resorptions.
Genotoxicity studies covering relevant genotoxicity endpoints showed no evidence of clastogenic or mutagenic activity. Administration of everolimus for up to 2 years did not indicate any oncogenic potential in mice and rats up to the highest doses, corresponding respectively to 3.9 and 0.2 times the estimated clinical exposure.
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