Safety considerations of mammalian target of rapamycin inhibitors in tuberous sclerosis complex and renal transplantation

Abstract

Rapamycin-related mTOR inhibitors (rapalogs) possess immunosuppressive and antiproliferative properties. Their mechanism of action makes them attractive therapies for several disease states but also potentiates adverse effects associated with these drugs. The oral mTOR inhibitor everolimus was recently approved for the treatment of tuberous sclerosis complex (TSC)-associated renal angiomyolipoma. As clinical use of rapalogs for the treatment of TSC increases, nephrologists and urologists who treat both children and adults with renal masses, as well as internists and geneticists with an interest in renal disease, should be aware of their safety profiles. This review presents the clinical experience of rapamycin-related mTOR inhibitors in patients with TSC and summarizes their toxicity profiles in renal transplant and TSC populations. Increased usage of rapalogs in a variety of patient populations demands vigilant monitoring of their safety profiles and rigorous differentiation between disease-specific and drug-specific toxicities.

Dose-level response rates of mTOR inhibition in tuberous sclerosis complex related subependymal giant cell astrocytoma

“…[20] Menstrual irregularities are reported in about a third of postmenarchal women treated with mTOR inhibitors but no longterm data are yet available with regard to a possible effect on fertility. [23] In this study, all six patients demonstrated SEGA tumor shrinkage of greater than 50% when treated with an mTOR inhibitor at therapeutic doses (4-5 mg/m 2 ), which is consistent with the existing evidence. However, the results demonstrate that sub-therapeutic doses of sirolimus (<2.5 mg/m 2 ) are not sufficient to maintain SEGA response on MRI.…”

“…In patients who have had transplants, sirolimus has been used in combination with other immunosuppressants since 1996 . Long‐term use of mTOR inhibitors in these patients is generally associated with toxicities that are more minor and easier to treat compared to other immunosuppressants . mTOR inhibitors have been introduced in the treatment of patients with TSC as early as 2004 and may be used for several indications in these patients.…”

“…One child had a temporary decrease in growth velocity as a result of significant loss of appetite, which was a consequence of the drug . Menstrual irregularities are reported in about a third of postmenarchal women treated with mTOR inhibitors but no long‐term data are yet available with regard to a possible effect on fertility …”

“…[22] Long-term use of mTOR inhibitors in these patients is generally associated with toxicities that are more minor and easier to treat compared to other immunosuppressants. [23] mTOR inhibitors have been introduced in the treatment of patients with TSC as early as 2004 [2] and may be used for several indications in these patients. Reports on long-term adverse events and experience in this context are still limited.…”

New perspectives on mTOR inhibitors (rapamycin, rapalogs and TORKinibs) in transplantation

“…It remains unclear whether the perioperative use of TORKinibs would be well tolerated and safe. More detailed elaboration on the safety considerations of mTOR inhibitors can be found in a recent review .…”