Everolimus

Everolimus belongs to a class of drugs called mTOR inhibitors, sometimes described as rapalogs because they are analogs of rapamycin ^[1][2]. It is a semisynthetic derivative of sirolimus (rapamycin), a compound originally isolated from a soil bacterium, modified by the addition of a hydroxyethyl group that improves its solubility and pharmacological handling ^[1]. It acts chiefly on one form of the mTOR complex, mTORC1, the cellular machinery that coordinates growth, division, and metabolism ^[1].

A major role of everolimus is in cancer treatment ^[1][2]. In a landmark placebo-controlled trial in advanced kidney cancer that had progressed despite other therapy, everolimus lengthened the time before the disease worsened, establishing it as a treatment option in that setting ^[3]. It is also approved for certain hormone-receptor-positive advanced breast cancers and for progressive neuroendocrine tumors; a pivotal trial in advanced pancreatic neuroendocrine tumors likewise showed that everolimus delayed disease progression compared with placebo ^[4]. In addition, it is used for the benign tumors and seizures associated with the genetic disorder tuberous sclerosis complex ^[1].

Beyond oncology, everolimus serves as an immunosuppressant to help prevent rejection of transplanted kidneys, livers, and hearts, often as part of combination regimens that allow lower doses of other immunosuppressive drugs ^[1][5]. Reviews of its use in transplant recipients describe both its benefits and its characteristic side effects ^[5]. A related application takes advantage of its ability to suppress cell proliferation: everolimus is used to coat certain drug-eluting coronary stents, where it helps prevent the re-narrowing of treated arteries ^[1].

Everolimus was developed by Novartis and approved for various indications beginning in the late 2000s, with different brand names used for its cancer, transplant, and tuberous sclerosis uses ^[1]. It is a prescription medicine taken as an oral tablet, generally once daily ^[1]. Common adverse effects include mouth sores (stomatitis), infections, diarrhea, fatigue, rash, and swelling, along with laboratory changes such as anemia, raised blood cholesterol, and elevated liver enzymes; a less common but serious risk is inflammation of the lungs ^[1]. Because it lowers the body's immune defenses, it can increase susceptibility to infection ^[1][5].

Everolimus is a potent immunosuppressant with significant risks including mouth ulcers, infections, high blood sugar and lipids, lung inflammation, and impaired wound healing. It requires prescription, monitoring, and medical supervision. It interacts with many drugs and is not appropriate for casual or unsupervised longevity experimentation.

Everolimus is a substrate of both CYP3A4 and P-glycoprotein, and the swings are extreme. Ketoconazole raised everolimus exposure roughly fifteen fold in healthy volunteers, so strong inhibitors, including clarithromycin, itraconazole, ritonavir and telithromycin, can push it well outside its therapeutic window into stomatitis, myelosuppression and non-infectious pneumonitis. Moderate inhibitors such as erythromycin, fluconazole, verapamil and diltiazem do the same on a smaller scale, as does grapefruit juice.

Inducers run the other way and threaten efficacy or, in transplant use, graft rejection. Rifampin cut exposure by about 63 percent, and carbamazepine, phenytoin, phenobarbital, efavirenz and St John's wort behave similarly.

Two interactions have nothing to do with metabolism. ACE inhibitors taken with everolimus raise the risk of angioedema several fold, an effect consistent across pooled trial data. And because everolimus suppresses the immune response, live vaccines given during treatment carry a risk of disseminated infection alongside a weakened antibody response.

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