everolimus

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Ligands
everolimus

GtoPdb Ligand ID: 5889

everolimus is an approved drug (FDA & EMA (2009))

Comment: Everolimus is a Type-3 kinase inhibitor and it was first approved by the FDA in 2009. There is some ambiguity in the literature as to the exact stereochemistry of everolimus. The structure shown here matches that in the Pubchem entry listed in the Database Links table. Other common representations include CID 46930999, CID 70789204 and CID 16211121 .

View interactive charts of activity data across species

View more information in the IUPHAR Pharmacology Education Project: everolimus

everolimus is commercially available from our sponsors

2D Structure

Physico-chemical Properties

Hydrogen bond acceptors	15
Hydrogen bond donors	3
Rotatable bonds	9
Topological polar surface area	204.66
Molecular weight	957.58
XLogP	4.13
No. Lipinski's rules broken	1

SMILES / InChI / InChIKey

Canonical SMILES	OCCOC1CCC(CC1OC)CC(C1OC(=O)C2CCCCN2C(=O)C(=O)C2(O)OC(CCC2C)CC(OC)C(=CC=CC=CC(CC(C(=O)C(C(C(=CC(C(=O)C1)C)C)O)OC)C)C)C)C
Isomeric SMILES	OCCO[C@@H]1CC[C@H](C[C@H]1OC)C[C@H]([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H](CC[C@H]2C)C[C@H](OC)/C(=C/C=C/C=C/[C@H](C[C@H](C(=O)[C@@H]([C@@H](/C(=C/[C@H](C(=O)C1)C)/C)O)OC)C)C)/C)C
InChI	InChI=1S/C53H83NO14/c1-32-16-12-11-13-17-33(2)44(63-8)30-40-21-19-38(7)53(62,68-40)50(59)51(60)54-23-15-14-18-41(54)52(61)67-45(35(4)28-39-20-22-43(66-25-24-55)46(29-39)64-9)31-42(56)34(3)27-37(6)48(58)49(65-10)47(57)36(5)26-32/h11-13,16-17,27,32,34-36,38-41,43-46,48-49,55,58,62H,14-15,18-26,28-31H2,1-10H3/b13-11+,16-12+,33-17+,37-27+/t32-,34-,35-,36-,38-,39+,40+,41+,43-,44+,45+,46-,48-,49+,53-/m1/s1
InChI Key	HKVAMNSJSFKALM-GKUWKFKPSA-N

No information available.

No information available.

Summary of Clinical Use
Everolimus is used as an immunosuppressant to prevent rejection of transplanted organs. Everolimus is being evaluated in a large number of clinical trials for its potential antineoplastic effect, as well as for its immunomodulatory activity in immune-related conditions. Click here to link to active everolimus trials registered with ClinicalTrials.gov. Oncology approval: In February 2016, the US FDA approved everolimus for the treatment of progressive, well-differentiated non-functional, neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin, in patients with unresectable, locally advanced or metastatic disease. Evidence is accumulating that links the mTOR pathway with ageing. A small trial in humans, addressing this issue by investigating the effect of everolimus on ability to generate antibodies in response to influenza vaccination in elderly volunteers (an immune function that declines with age), reports an improved response following drug treatment [1]. Further studies are required to assess the potential for mTOR inhibition to improve other aging-related conditions. In April 2018, the FDA approved an oral formulation of everolimus, Afinitor Disperz, as an adjunctive treatment for tuberous sclerosis complex (TSC)-associated partial-onset seizures. Theis approval also permits use of everolimus to treat TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated renal angiomyolipoma.

Summary of Clinical Use

Everolimus is used as an immunosuppressant to prevent rejection of transplanted organs.

Everolimus is being evaluated in a large number of clinical trials for its potential antineoplastic effect, as well as for its immunomodulatory activity in immune-related conditions. Click here to link to active everolimus trials registered with ClinicalTrials.gov.

Oncology approval: In February 2016, the US FDA approved everolimus for the treatment of progressive, well-differentiated non-functional, neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin, in patients with unresectable, locally advanced or metastatic disease.

Evidence is accumulating that links the mTOR pathway with ageing. A small trial in humans, addressing this issue by investigating the effect of everolimus on ability to generate antibodies in response to influenza vaccination in elderly volunteers (an immune function that declines with age), reports an improved response following drug treatment [1]. Further studies are required to assess the potential for mTOR inhibition to improve other aging-related conditions.
In April 2018, the FDA approved an oral formulation of everolimus, Afinitor Disperz, as an adjunctive treatment for tuberous sclerosis complex (TSC)-associated partial-onset seizures. Theis approval also permits use of everolimus to treat TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated renal angiomyolipoma.

Mechanism Of Action and Pharmacodynamic Effects
Inhibitor of the serine-threonine kinase mammalian target of rapamycin (mTOR), inhibiting only mTORC1. Everolimus binds to intracellular FK506 binding protein-12 (FKBP-12) resulting in an inhibitory complex formation and inhibition of mTOR kinase activity. Everolimus also inhibits the expression of hypoxia-inducible factor, leading to a decrease in the expression of VEGF. The overall result of this inhibition is reduction of the activity of downstream effectors leading to an inability of cells to progress from G1 into S phase, a reduction in cell proliferation, angiogenesis, and glucose uptake and apoptosis.

Mechanism Of Action and Pharmacodynamic Effects

Inhibitor of the serine-threonine kinase mammalian target of rapamycin (mTOR), inhibiting only mTORC1. Everolimus binds to intracellular FK506 binding protein-12 (FKBP-12) resulting in an inhibitory complex formation and inhibition of mTOR kinase activity. Everolimus also inhibits the expression of hypoxia-inducible factor, leading to a decrease in the expression of VEGF. The overall result of this inhibition is reduction of the activity of downstream effectors leading to an inability of cells to progress from G1 into S phase, a reduction in cell proliferation, angiogenesis, and glucose uptake and apoptosis.

Pharmacokinetics
Absorption/Distribution
In patients with advanced solid tumours, peak everolimus concentrations (C_max) are reached 1-2 hours after oral doses ranging between 5 and 70 mg everolimus under fasting conditions or with a light fat-free snack. Steady-state is achieved within 2 weeks following once-daily dosing. The blood-to-plasma ratio of everolimus is 17% to 73% and approximately 74% is protein bound in both healthy patients and those with moderate hepatic impairment.
Biotransformation/Metabolism
Everolimus is a substrate for CYP3A4 and P-glycoprotein (P-gp). Six primary metabolites have been identified in human blood. Everolimus is considered to contribute the majority of the overall pharmacological activity as its metabolites are approximately 100 times less active than the parent drug.
Elimination
No specific excretion studies have been undertaken in cancer patients. Data are available from studies in transplant patients with elimination occurring via feces (80%) and urine (5%).
Population pharmacokinetics
No significant influence of age (27-85 years) or gender on oral clearance of everolimus has been reported. Average exposure is higher in Japanese patients compared with non-Japanese patients and oral clearance is 20% higher in black patients compared with white patients, although the relevance of these differences for safety and efficacy has not been established.
Organ function impairment
Dose adjustment is recommended for patients with hepatic impairment based on their Child-Pugh status. In patients with advanced solid tumours no significant influence of creatinine clearance (25-178 ml/min) was detected on clearance/bioavailability of everolimus. Post-transplant renal impairment (creatinine clearance range 11-107 ml/min) did not affect the pharmacokinetics of everolimus in transplant patients, although it has been estimated that these patients will clear 0.33% less of the administered dose over one year compared to non-transplant patients.

Pharmacokinetics

Absorption/Distribution

In patients with advanced solid tumours, peak everolimus concentrations (C_max) are reached 1-2 hours after oral doses ranging between 5 and 70 mg everolimus under fasting conditions or with a light fat-free snack. Steady-state is achieved within 2 weeks following once-daily dosing. The blood-to-plasma ratio of everolimus is 17% to 73% and approximately 74% is protein bound in both healthy patients and those with moderate hepatic impairment.

Biotransformation/Metabolism

Everolimus is a substrate for CYP3A4 and P-glycoprotein (P-gp). Six primary metabolites have been identified in human blood. Everolimus is considered to contribute the majority of the overall pharmacological activity as its metabolites are approximately 100 times less active than the parent drug.

Elimination

No specific excretion studies have been undertaken in cancer patients. Data are available from studies in transplant patients with elimination occurring via feces (80%) and urine (5%).

Population pharmacokinetics

No significant influence of age (27-85 years) or gender on oral clearance of everolimus has been reported. Average exposure is higher in Japanese patients compared with non-Japanese patients and oral clearance is 20% higher in black patients compared with white patients, although the relevance of these differences for safety and efficacy has not been established.

Organ function impairment

Dose adjustment is recommended for patients with hepatic impairment based on their Child-Pugh status. In patients with advanced solid tumours no significant influence of creatinine clearance (25-178 ml/min) was detected on clearance/bioavailability of everolimus. Post-transplant renal impairment (creatinine clearance range 11-107 ml/min) did not affect the pharmacokinetics of everolimus in transplant patients, although it has been estimated that these patients will clear 0.33% less of the administered dose over one year compared to non-transplant patients.