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Advanced Neurology mTOR inhibition in epilepsy

Table 1. (Continued)
Rapamycin (Sirolimus) 51 Everolimus 52‑54 Temsirolimus 55
Pharmacokinetics • Tmax, oral solution: 2.1 h (adult); • Tmax, oral: 1 – 3 h (transplant), 1 – 2 h • Tmax, Temsirolimus:
5.88 h (age 6 to 11 y); 2.7 h (age 12 y (advanced solid tumors) 0.5 h (1 – 2.5 h
or older) • Bioavailability: 20 – 36% sirolimus, primary
• Tmax, oral tablet: 3.5 h (adult) • Protein binding: 74% metabolite)
• Bioavailability, oral: 14% (solution), • Vd: 107 – 342 L • Vd: 172 L
>27% than solution (tablet) • Metabolism: liver, extensive, substrate of CYP3A4 and • Metabolism: hepatic,
• Protein binding: 92% P-glycoprotein substrate of CYP3A4
• Vd: 12 L/kg • Excretion: renal 5%, feral 80%, elimination half‑life • Excretion: renal
• Metabolism: 7 major metabolites, 30 h, 79 h (hepatic impairment) 4.6%, fecal 78%,
substrate of CYP3A4 and total body clearance
P-glycoprotein 16.2 L/h (adult),
• Excretion: renal 2.2%, feral 91%, elimination half-life
elimination half-life 61.3 h (female), 17.3 h (adults), 31 h
72.3 h (male) (children)
Adverse reactions a • Renal transplant rejection • Breast cancer, NET, RCC: stomatitis, infections, rash, • Rash, asthenia,
prophylaxis: peripheral edema, fatigue, diarrhea, edema, abdominal pain, nausea, fever, mucositis, nausea,
dyslipidemia, hypertension, elevated asthenia, cough, headache, anorexia edema, anorexia
creatinine, abdominal pain, diarrhea, • TSC‑associated renal AML: stomatitis • Anemia,
headache, fever, urinary tract • TSC‑associated SEGA: stomatitis, respiratory tract infection hyperglycemia,
infection, anemia, nausea, arthralgia, • TSC‑associated partial‑onset seizures: stomatitis dyslipidemia,
pain, thrombocytopenia elevated alkaline
• Pulmonary LAM: stomatitis, phosphate, elevated
diarrhea, abdominal pain, nausea, serum creatinine,
nasopharyngitis, acne, chest pain, lymphopenia,
peripheral edema, upper respiratory hypophosphatemia,
tract infection, headache, dizziness, thrombocytopenia,
myalgia, hypercholesterolemia elevated AST,
• TSC‑associated facial angiofibroma: leukopenia
dry skin, local irritation, pruritus,
acne, acneiform dermatitis, ocular
hyperemia, skin hemorrhage
Note: The most common adverse reaction with incidence ≥30%, except for topical sirolimus with an adverse effect incidence of ≥1%.
a
Abbreviations: AML: Angiomyolipoma; CYP: Cytochrome; FDA: United States Food and Drug Administration; GI: Gastrointestinal; IV: Intravenous;
LAM: Lymphangioleiomyomatosis; NET: Neuroendocrine tumor; PEComa: Perivascular epithelioid cell tumor; POD: Post-operation day; RCC: Renal
cell carcinoma; SEGA: Subependymal giant cell astrocytoma; Tmax: Time to maximum concentration; TSC: Tuberous sclerosis complex; Vd: Volume of
distribution; qd: Once a day; bid: Twice a day; y: Year.

rapamycin has not been established for children younger Everolimus is one of the most extensively studied mTOR
than 13 years old. 51 inhibitors in clinical settings, particularly in the treatment
Rapamycin has poor solubility and pharmacokinetic of tuberous sclerosis complex. 64
properties, limiting its use for other indications, such as Everolimus was first approved by the U.S. FDA in 2010
epilepsy. Rapamycin derivatives, or rapalogs, such as for the treatment of surgically inaccessible SEGA in adults
59
temsirolimus, everolimus, and ridaforolimus, act similarly and children aged ≥3 years. This approval was expanded in
as allosteric mTOR inhibitors but have been modified at 2012 to include children aged above 1 year, with a newly
53
the C-42 position of rapamycin to improve solubility, developed pediatric drug formulation (Table 1). The
stability, and bioavailability. 59 effects of everolimus on tuberous sclerosis complex-related
epilepsy have since been investigated in various clinical
6.1.2. Everolimus trials (Table 2). 65-68
Everolimus, chemically known as 40-O-(2-hydroxyethyl)- The first prospective, open-label clinical trial focused
rapamycin, is a derivative of rapamycin in which the on everolimus use in tuberous sclerosis complex-related
hydroxyl group at the C-40 position is substituted by epilepsy was conducted by Krueger et al. In this study,
67
a hydroxyl ethyl group. This modification improves its 20 patients were treated with everolimus for 12 weeks
pharmacokinetic properties, providing higher solubility, without any titration of their concurrent anti-seizure
increased oral bioavailability, and a shorter half-life. medication. The results showed a significant median
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Volume 3 Issue 3 (2024) 8 doi: 10.36922/an.3568