Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Novartis South Africa (Pty) Ltd, Magwa Crescent West, Waterfall City, Jukskei View, Johannesburg, 2090
A 34 Other: Selective immunosuppressive agents.
Everolimus is an inhibitor targeting mTOR (mammalian target of rapamycin), or more specifically, mTORC1 (mammalian ‘target of rapamycin’ complex 1). It exerts its activity through high affinity interaction with the intracellular receptor protein FKBP12. The FKBP12/everolimus complex binds to mTORC1, inhibiting its signalling capacity. mTOR is a key serine-threonine kinase playing a central role in the regulation of cell growth, proliferation and survival. Inhibition of mTORC1 by everolimus has been shown to reduce cell proliferation, glycolysis and angiogenesis in solid tumours in vivo, both through direct antitumour cell activity and inhibition of the tumour stromal compartment. mTORC1 signalling is affected through modulation of the phosphorylation of downstream effectors, the best characterized of which are the translational regulators S6 ribosomal protein kinase (S6K1) and eukaryotic initiation factor 4E-binding protein (4E-BP). Disruption of S6K1 and 4E-BP1 function, as a consequence of mTORC1 inhibition, interferes with the translation of mRNAs encoding pivotal proteins involved in cell cycle regulation, glycolysis and adaptation to low oxygen conditions (hypoxia). This inhibits tumour growth and expression of hypoxia-inducible factors (e.g. HIF-1 transcription factors); the latter resulting in reduced expression of factors involved in the potentiation of tumour angiogenic processes (e.g. the vascular endothelial growth factor VEGF) in multiple tumours such as RCC and angiomyolipoma).
Two primary regulators of mTORC1 signalling are the oncogene suppressors tuberin-sclerosis complexes 1 & 2 (TSC1, TSC2). Loss or inactivation 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 S6K1.
A substrate of mTOR complex 1(mTORC1), S6K1 phosphorylates the oestrogen receptor, which is responsible for ligand-independent receptor activation. In tuberous sclerosis syndrome, a genetic disorder, inactivating mutations in either the TSC1 or the TSC2 gene lead to hamartoma formation throughout the body.
Everolimus is a potent inhibitor of the growth and proliferation of tumour cells, endothelial cells, fibroblasts and blood vessel-associated smooth muscle cells. Consistent with the central regulatory role of mTORC1, everolimus has been shown to reduce tumour cell proliferation, glycolysis and angiogenesis in solid tumours in vivo, and thus provides two independent mechanisms for inhibiting tumour growth: direct antitumor cell activity and inhibition of the tumour stromal compartment.
Activation of the mTOR pathway is a key adaptive change driving endocrine resistance in breast cancer. Various signal transduction pathways are activated to escape the effect of endocrine therapy. One pathway is the P13K/Akt/mTOR pathway, which is constitutively activated in aromatase inhibitor (A1)- resistant and long- term oestrogen deprived breast cancer cells. In breast cancer cells, resistance due to A1s due to Akt activation can be reversed by co-administration with everolimus.
There was a moderate correlation between the decrease in the phosphorylation of 4E-BP1 (P4-EBP1) in tumour tissue and the average everolimus C min at steady state in blood after daily administration of 5 or 10 mg everolimus. Further data suggest that the inhibition of phosphorylation of the S6 kinase is very sensitive to the mTOR inhibition by everolimus.
Inhibition of phosphorylation of elF-4G was complete at all C min values after the 10 mg daily dose.
RADIANT-4 (Study CRAD001T2302), a randomized, double-blind, multicentre phase III study of Everolimus plus best supportive care (BSC) versus placebo plus best supportive care was conducted in patients with advanced non-functional neuroendocrine tumours (NET) of gastrointestinal or lung origin without a history of and no active symptoms related to carcinoid syndrome. The primary endpoint for the study was progression-free survival (PFS) evaluated by Response Evaluation Criteria in Solid Tumours (modified RECIST version 1.0), based on independent radiological assessment. Supportive PFS analysis was based on local investigator review. Secondary endpoints included overall survival (OS), Overall Response Rate (ORR), Disease Control Rate (DCR = proportion of patients with a best overall response of complete response, partial response or stable disease), Safety, change in Quality of Life (QoL) via FACT-G and time to WHO PS deterioration. A total of 302 patients were randomized in a 2:1 ratio to receive either everolimus (10 mg daily) (n=205) or placebo (n=97). The two treatment groups were generally balanced with respect to the baseline demographics, disease characteristics and history of prior somatostatin analogue (SSA) use. The efficacy results were obtained from the final analysis of PFS after 178 PFS events were observed per independent radiological review.
The study demonstrated a statistically significant clinical benefit of everolimus over placebo by a 2.8-fold prolongation in median PFS (11.01 months versus 3.91 months), resulting in a 52% risk reduction of progression or death (HR 0.48; 95% CI: 0.35, 0.67; one-sided stratified log-rank test p-value <0.001) per independent assessment. The analysis of PFS based on local investigator assessment was supportive and showed a 2.6-fold prolongation in median progression-free-survival (14.39 months versus 5.45 months), resulting in a 60% risk reduction of progression or death (HR 0.40; 95% CI: 0.29, 0.55; one-sided stratified log-rank test p-value<0.001). The overall response rate as per independent assessment was 2% in the everolimus arm vs. 1% in the placebo arm. Disease control rate (CR or PR or SD) for everolimus was 82.4% vs. 64.9% in the placebo arm. Results also indicate that 63.6% of patients in the everolimus arm experienced tumour shrinkage versus 25.9% for placebo.
The final overall survival (OS) analysis did not show statistically significant difference between those patients who received everolimus or placebo during the blinded treatment period of the study [HR= 0.90 (95% CI: 0.66 to 1.24)].
In patients with advanced solid tumours, peak everolimus concentrations are reached 1 to 2 hours after administration of an oral dose of 5 to 710 mg everolimus under fasting conditions or with a light fat-free snack. Cmax is dose-proportional between 5 and 10 mg. At doses of 20 mg/week and higher, the increase in Cmax is less than dose- proportional, however AUC shows dose-proportionality over the 5 to 70 mg dose range.
In healthy subjects, high fat meals reduced systemic exposure to AFINITOR 10 mg (as measured by AUC) by 22% and the peak plasma concentration Cmax by 54%. Light fat meals reduced AUC by 32% and Cmax by 42%. Food, however, had no apparent effect on the post absorption phase concentration time profile.
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%. The amount of everolimus confined to the plasma is approximately 20% at blood concentrations observed in cancer patients given everolimus 10 mg/day. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment.
Following intravenous administration in a rat model, everolimus was shown to cross the blood-brain barrier in a non-linear dose-dependent manner, suggesting saturation of an efflux pump at the blood- brain barrier. Brain penetration of everolimus has also been demonstrated in rats receiving oral doses of everolimus.
Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, it 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, the parent substance is considered to contribute the majority of the overall pharmacological activity of everolimus.
No specific excretion studies have been undertaken in cancer patients; however, data are available from the transplantation setting. Following the administration of a single dose of radiolabelled everolimus in conjunction with ciclosporine, 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 daily or weekly administration of everolimus in patients with advanced solid tumours, steady-state AUC0-τ was dose-proportional over the range of 5 to 10 mg in the daily dosing regimen and 5 to 70 mg on the weekly regimen. Steady state was achieved within two weeks with the daily dosing regimen. Cmax is dose-proportional between 5 and 10 mg on the daily and weekly regimens. At doses of 20 mg/week and higher, the increase in Cmax is less than dose-proportional 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 on the daily regimen. The mean elimination half-life of everolimus is approximately 30 hours.
The safety, tolerability and pharmacokinetics were evaluated in a single oral dose study of everolimus in 34 subjects with impaired hepatic function relative to subjects with normal hepatic function. Compared to normal subjects, there was a 1,6-fold, 3,3-fold and 3,6-fold increase in exposure (i.e. AUC(0-inf) for subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, respectively. Simulation of multiple dose pharmacokinetics supports the dosing recommendations in hepatic impaired patients based on their Child-Pugh status. Dose adjustment is recommended for patients with hepatic impairment (see sections 4.2 and 4.4).
In a population pharmacokinetic analysis of 170 patients with advanced cancer, no significant influence of creatinine clearance (25 to 178 ml/min) was detected on CL/F of everolimus. Post-transplant renal impairment (creatinine clearance range 11 to 107 ml/min) did not affect the pharmacokinetics of everolimus in transplant patients.
Everolimus has not been studied in children with renal carcinoma.
In a population pharmacokinetic evaluation in cancer patients, no significant influence of age (27 to 85 years) on oral clearance (CL/F: range 4,8 to 54,5 litres/hour) 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, oral clearance (CL/F) is on average 20% higher in black transplant patients.
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