Recent Advances and Challenges of mTOR Inhibitors Use in the Treatment of Patients with Tuberous Sclerosis Complex

Table 1

Pharmacology and clinical applications of rapamycin (sirolimus) and its analogues, everolimus, temsirolimus, and ridaforolimus.

​	Sirolimus	Everolimus	Temsirolimus	Ridaforolimus
Commercial names	Rapamune®	Afinitor®, Votubia®, Certican®, Zortress®, Evertor®	CCI-779, Torisel®	AP23573, MK-8669, Deforolimus
Biochemical features	​	​	​	​
Molecular weight	914.2 g/mol	958.2 g/mol	1030.3 g/mol	990.2 g/mol
Mechanism of action	Inhibition of the TSC-mTOR pathway	Inhibition of the TSC-mTOR pathway	Inhibition of the TSC-mTOR pathway	Inhibition of the TSC-mTOR pathway
Biochemically functional form	Sirolimus is the active form	Active derivative (hydroxyethyl ester) of sirolimus	Prodrug actived after removal of the dihydroxymethyl propionic acid ester group at C40 position	Active derivative (dimethylphosphinate) of sirolimus
Pharmacokinetic features	​	​	​	​
Route of administration	Orally, once daily	Orally, once daily	I.V. infusion, once/week	Oral or intravenous infusion
Protein binding	~92%	~75%	~85%	~94%
Bioavailability and distribution	Low oral bioavailability (~15%): 14% for solution and 18% for tablets; Large distribution (around 12 L/kg), ~95% into RBCs	Tablet: 20%; Wide distribution into RBCs; good blood-brain partition coefficient	Injection: 100%; Elevated distribution that allows extensive delivery into peripheral tissues	Tablet: 16%; Improved solubility, stability and bioavailability vs sirolimus
Metabolization	Hepatic CYP3A	Hepatic CYP3A	Hepatic CYP3A4	Hepatic CYP3A4
Terminal half-life	46–78 h	26–30 h	9–27 h	30–75 h
Elimination	Feces (91%), urine (2%)	Feces (>90%), urine (2%)	Feces (82%), urine (5%)	Feces (88%), urine (2%)
Clinical indications	​	​	​	​
In TSC patients and other indications	Clinical trials in TSC patients; immunosuppression in transplanted patients	SEGA and adult angiomyolipoma associated with TSC; immunosuppression in transplanted patients; advanced kidney cancer and other tumors (neuroendocrine, breast)	Advanced renal cell cancer	Clinical trials for advanced soft tissue and bone sarcomas and hematologic malignancies