Everolimus

Absorption

In patients with advanced solid tumors, peak everolimus concentrations are reached 1 to 2 hours after administration of oral doses ranging from 5 mg to 70 mg. Following single doses, Cmax is dose-proportional between 5 mg and 10 mg. At doses of 20 mg and higher, the increase in Cmax is less than dose-proportional, however AUC shows dose-proportionality over the 5 mg to 70 mg dose range. Steady-state was achieved within 2 weeks following once-daily dosing. Dose Proportionality in Patients with SEGA (subependymal giant-cell astrocytomas) and TSC (tuberous sclerosis complex): In patients with SEGA and TSC, everolimus Cmin was approximately dose-proportional within the dose range from 1.35 mg/m2 to 14.4 mg/m2.

Toxicity

IC50 of 0.63 nM.

Description

Everolimus, an oral immunosuppressant for the treatment of kidney and heart transplant rejection, is the 40-O-(2-hydroxyethyl) derivative of rapamycin. It has immunosuppressive properties similar to those of rapamycin, but with improved pharmacokinetic profile. Everolimus, like rapamycin, is a proliferation signal inhibitor that exerts its immunosuppressive effect by inhibiting the activation of p70 S6 kinase, thereby blocking growth factor-driven proliferation of T cells, B cells and vascular smooth muscle cells, and arresting cell cycle at the G1 phase. Inhibition of p70 S6 kinase activation by everolimus and rapamycin is mediated by their binding to FKBP12 (FK506 binding-protein 12). Everolimus inhibits FK506 binding to FKBP12 with an IC50 of 1.8–2.6 nM, and it is about 3- to 5-fold less potent than rapamycin (IC50=0.4–0.9 nM). The in vitro immunosuppressive activity of everolimus is also slightly less than that of rapamycin as demonstrated in a mixed lymphocyte reaction (MLR) assay (IC50=0.2–1.6 nM versus 0.07–0.5 nM, respectively) and in antigen-specific human helper T-cell clones (IC50=0.05–0.17nM versus 0.014–0.37nM, respectively). However, the in vivo immunosuppressive activity of oral everolimus 1–5 mg/ kg/day is similar to that of rapamycin at equivalent doses in rat models of renal or cardiac transplantation, localized graft-versus-host disease, and autoimmune glomerulonephritis. The recommended dosage of everolimus is 0.75 mg twice daily, and it is used in combination with cyclosporine microemulsion and corticosteroids.

Chemical properties

Off White Solid

Originator

Novartis (Switzerland)

The Uses of Everolimus

Everolimus (IX) (SDZ-RAD), was developed by Novartis as an immunosuppressant to be used in conjunction with cyclosporin in transplantation allograft rejection and was recently approved in the US in 2003. Another natural product that had been approved for use in transplantation is rapamycin (sirolimus) as an inejectable agent. In an attempt to develop an orally bioavailable immunosuppressant agent, many companies attempted modification of rapamycin itself.

The Uses of Everolimus

Macrolide immunosuppressant; derivative of Rapamycin. Inhibits cytokine-mediated lymphocyte proliferation

The Uses of Everolimus

Everolimus is a semi-synthetic macrocyclic lactone prepared from rapamycin by selective alkylation of the 42-hydroxy group with a silyl-protected hydroxyethyl triflate moiety, followed by addition of an ethylhydroxy moiety to provide greater stability and bioavailability. Like all tacrolimus analogues, everolimus binds to receptor protein, FKBP12. The complex then binds to mTOR preventing it from interacting with target proteins. Everolimus is extensively cited in the literature with over 2,000 citations.

Indications

Everolimus is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. Indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease. Indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. Indicated for the treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. Indicated in pediatric and adult patients with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.

Background

Everolimus is a derivative of Rapamycin (sirolimus), and works similarly to Rapamycin as an mTOR (mammalian target of rapamycin) inhibitor. It is currently used as an immunosuppressant to prevent rejection of organ transplants. In a similar fashion to other mTOR inhibitors Everolimus' effect is solely on the mTORC1 protein and not on the mTORC2 protein.

What are the applications of Application

Everolimus is an immunosuppresive inhibitor of FRAP (mTOR)

Definition

ChEBI: Everolimus is a macrocyclic lactone that is rapamycin in which the hydroxy group attached to the cyclohexyl moiety has been converted into the corresponding 2-hydroxyethyl ether. It is an immunosuppressant and antineoplastic agent. It has a role as an antineoplastic agent, an immunosuppressive agent, a mTOR inhibitor, an anticoronaviral agent and a geroprotector. It is a primary alcohol, a secondary alcohol, an ether, a cyclic ketone, a cyclic acetal and a macrolide lactam. It is functionally related to a member of sirolimus.

brand name

Certican

General Description

Everolimus, sold under trade names including Zortress^?, Certican, and Afinitor^?, is an immunosuppressant drug used to prevent rejection of organ transplants and to treat renal cell cancer and other tumors. This Certified Spiking Solution^? is suitable as starting material for calibrators, controls, or linearity standards for therapeutic drug monitoring or clinical and diagnostic testing of everolimus in patient whole blood samples by LC-MS/MS.

Biological Activity

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that, as part of two distinct complexes (mTORC1 and mTORC2), plays pivotal roles in intracellular signaling. Everolimus is a hydroxyethyl ether rapamycin derivative that inhibits mTOR signaling through both mTORC1 and mTORC2 when added to cells at 20 nM. It is orally available and shows improved pharmacokinetics and pharmacodynamics over rapamycin. Through its inhibition of mTOR, everolimus inhibits cell proliferation, metabolism, and angiogenesis in certain types of cancer. It also acts as an immunosuppressive agent in the context of organ transplantation.

Biochem/physiol Actions

Everolimus, the 40-O-(2-hydroxyethyl) derivative of rapamycin (sirolimus), is a potent and selective inhibitor of mechanistic target of rapamycin (mTOR). Everolimus is selective for the mTORC1 protein complex. Everolimus exhibit potent immunosuppressive and anticancer activities.

Synthesis

Everolimus (IX) was discovered by Sandoz (Novartis) scientists by modifying rapamycin drug in the 40-hydroxyl position. Thus, treatment of rapamycin (84) with t-butyldimethylsilyloxy ethyl triflate in the presence of 2,6-lutidine at 60??C for 3.5 hrs gave ether 85. Deprotection of the silyl group was done by treating silyloxy ether 85 in methanol with 2N HCl to give the product IX (everolimus), which was purified by chromatography. No yields were given for the reactions.

Drug interactions

Potentially hazardous interactions with other drugs
ACE-Is: increased risk of angioedema.
Antibacterials: erythromycin, clarithromycin and telithromycin increase everolimus levels - avoid with clarithromycin and telithromycin; rifampicin decreases everolimus levels by factor of 3.
Antidepressants: St John’s wort decreases everolimus levels.
Antifungals: concentration increased by ketoconazole and possibly itraconazole, posaconazole and voriconazole - avoid.
Antipsychotics: increased risk of agranulocytosis with clozapine - avoid.
Antivirals: concentration possibly increased by atazanavir, darunavir, indinavir, ritonavir and saquinavir - avoid; concentration significantly increased by dasabuvir and ombitasvir/paritaprevir/ ritonavir - avoid concomitant use.
Calcium channel blockers: concentration of both drugs increased with verapamil.
Ciclosporin: increases everolimus AUC by 168% and Cmax by 82%.
Cytotoxics: concentration increased by imatinib - consider reducing everolimus dose.
Grapefruit juice: increases everolimus levels.

Metabolism

Everolimus is a substrate of CYP3A4 and PgP (phosphoglycolate phosphatase). Three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus were the 6 primary metabolites detected in human blood. In vitro, everolimus competitively inhibited the metabolism of CYP3A4 and was a mixed inhibitor of the CYP2D6 substrate dextromethorphan.

Metabolism

Everolimus is metabolised in the liver and to some extent in the gastrointestinal wall, and is a substrate of P-glycoprotein and the cytochrome P450 isoenzyme CYP3A4. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ringopened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were shown to have approximately 100 times less activity than everolimus itself. Following the administration of a single dose of radiolabelled everolimus, 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.

storage

Store at -20°C

References

1) Schuurman et al. (1997), SDZ RAD, a new rapamycin derivative: synergism with cyclosporine; Transplantation, 64 32 2) Neuhaus et al. (2001), mTOR inhibitors: an overview; Liver Transpl., 7 473 3) Kahan et al. (2002), Therapeutic drug monitoring of immunosuppressant drugs in clinical practice; Clin. Ther., 24 330