Table 2.
Pharmacological Characterization, Clinical Indications and Adverse Effects of mTOR Inhibitors for Tuberous Sclerosis Complex Treatment (Adapted from Palavra F et al5)
| Sirolimus (Rapamycin) | Everolimus | |
|---|---|---|
| Molecular weight | 914.2 g/mol | 958.2 g/mol |
| Biochemically functional form | Active form | Active derivative (hydroxyethyl ester) of sirolimus |
| Route of administration | Orally, once daily Topic (concentrations 0.1% to 1%) |
Orally, once daily |
| Protein binding | ∼92% | ∼75% |
| Bioavailability and distribution | Low oral bioavailability (solution:14%; tablet: 18%) Large distribution (around 12 L/kg), ∼95% into RBCs |
Tablet: 20% Wide distribution into RBCs; good blood-brain partition coefficient |
| Metabolization | Hepatic CYP3A4, glycoprotein 1 | CYP3A4, CYP3A5, CYP2C8 |
| Terminal half-life | 46–78 h | 26–30 h |
| Elimination | Feces (91%), urine (2%) | Feces (>90%), urine (2%) |
| Clinical indications for TSC | Approved for severe-to-moderate LAM. Proved regression of kidney and liver angiomyolipomas, SEGAs, and seizures frequency. Topical formulation for facial angiofibromas. |
Approved for SEGA and adult angiomyolipoma associated with TSC. |
| Common adverse reactions | GI effects (constipation, abdominal pain, diarrhea), peripheral oedema, hypertension, hypertriglyeridaemia, hypercholesterolaemia, creatinine increase, anaemia, thrombocytopaenia, urinary tract infection, arthralgia, headache, fever Irritation and burning sensation after topical administration. |
Stomatitis, infections, rash, fatigue, diarrhea, hypercholesterolaemia, hyperglycaemia, hypertriglyceridaemia. elevated transaminases, anaemia, leukopenia, thrombocytopenia and lymphopenia. |
Notes: Adapted from Palavra F, Robalo C, Reis F. Recent advances and challenges of mTOR inhibitors use in the treatment of patients with tuberous sclerosis complex. Oxid Med Cell Longev. 2017;2017:9820181. Copyright © 2017 Filipe Palavra et al. This is an open access article distributed under the Creative Commons Attribution License.5
Abbreviations: RBCs, red blood cells; CYP3A, intestinal cytochrome p450 3 A enzymes; SEGA, subependymal giant cell astrocytomas; GI, gastrointestinal.