mTOR Inhibitors

Inhibitors of the mammalian target of rapamycin (mTOR) such as rapamycin (sirolimus) and its analogues (e.g. everolimus) have been shown to have potent immunosuppressive activity and also have known anti-cancer effects which have been exploited in clinical trials (Meric-Bernstam and Gonzalez-Angulo, 2009; Dufour et al., 2011). They are currently estimated to be prescribed in approximately 4% of liver transplant patients from the time of transplant while about 6% of patients receive them as part of maintenance treatment at 1-year post-transplant (Nashan, 2018).

While the chemical structure of sirolimus and everolimus are similar, in many ways they behave quite differently upon administration. The addition of a hydroxyethyl group confers on everolimus a different tissue and subcellular distribution and different affinities to active drug transporters and drug-metabolising enzymes. Furthermore, it has a much higher potency for interacting with the mTOR complex 2 than sirolimus as well as higher bioavailability and a shorter terminal half-life. While both compounds effectively induce immunosuppression, everolimus also has the potential to inhibit the negative effects of CNIs on neuronal and kidney cell metabolism, which sirolimus enhances (Klawitter et al., 2015). Sirolimus and everolimus should, therefore, not be considered interchangeable (Nashan et al., 2018).

A significant number of studies are exploring the use of mTOR inhibitors as CNI-sparing agents (De Simone et al., 2012). While these are being investigated for their ability to reduce the renal impact of CNIs, mTOR inhibitors have also been associated with a number of adverse effects including hyperlipidaemia, thrombocytopenia, aggravation of proteinuria, skin lesions, mouth ulcers, pneumonitis, and impaired wound healing (Kern and Sucher, 2012).

However, a recent study has shown that post-transplant patients have a lower incidence of malignancy when treated with mTOR inhibitors no matter if they were used with CNIs or not. The beneficial effects remain significant even when non-melanoma skin cancer are excluded (Wolf et al., 2018).