Everolimus (Mechanism of Action)

In this article, we will discuss Everolimus (Mechanism of Action). So, let’s get started.

Mechanism of Action

Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers. Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation (mTORC1) and thus inhibition of mTOR kinase activity. Everolimus reduced the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4E-BP1), downstream effectors of mTOR, involved in protein synthesis. In addition, everolimus inhibited the expression of hypoxia-inducible factor (e.g., HIF-1) and reduced the expression of vascular endothelial growth factor
(VEGF). Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies. Two regulators of mTORC1 signaling are the oncogene suppressors tuberin-sclerosis complexes 1 and 2 (TSC1, TSC2). Loss or inactivation of either TSC1 or TSC2 leads to activation of downstream signaling. In tuberous sclerosis (TS), a genetic disorder, inactivating mutations in either the TSC1 or the TSC2 gene lead to hamartoma formation throughout the
body.

Pharmacodynamics

QT/QTc Prolongation Potential

In a randomized, placebo-controlled, crossover study, 59 healthy subjects were administered a single oral dose of
Everolimus (20 mg and 50 mg) and placebo. There is no indication of a QT/QTc prolonging effect of Everolimus in
single doses up to 50 mg.

Exposure Response Relationships

Markers of protein synthesis show that inhibition of mTOR is complete after a 10 mg daily dose. In patients with SEGA, higher everolimus trough concentrations appear to be associated with larger reductions in SEGA volume. However, as responses have been observed at trough concentrations as low as 3 ng/mL, once acceptable efficacy has been achieved, additional dose increase may not be necessary.

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