everolimus

Ligand id: 5889

Name: everolimus

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Structure and Physico-chemical Properties

2D Structure
Calculated 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

Molecular properties generated using the CDK

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.<
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 (Cmax) 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.
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