mTOR Inhibitors

Inhibitors of the mammalian target of rapamycin (mTOR), such as rapamycin (sirolimus), and its analogues, such as everolimus, have been shown to have potent immunosuppressive activity. They also have known anti-cancer effects (Meric-Bernstam & Gonzalez-Angulo, 2009; Dufour et al., 2011). It is estimated that mTOR inhibitors are 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).

Although the chemical structures of sirolimus and everolimus are similar, they behave very differently upon administration. Due to the addition of a hydroxyethyl group, everolimus has a different tissue and subcellular distribution to sirolimus, as well as 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 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). As a result of these differences, sirolimus and everolimus should not be considered interchangeable (Nashan et al., 2018).

The most common adverse effects of mTOR inhibitors are hyperlipidaemia, thrombocytopenia, aggravation of proteinuria, skin lesions, mouth ulcers, pneumonitis, and impaired wound healing (Kern & Sucher, 2012).

Pneumonitis is the most important and life-threatening adverse effect of mTOR inhibitors, with an incidence of 1.3% to 12.7% in renal transplant recipients. It generally develops within 1 year, usually within the first 3 months after an mTOR inhibitor is initiated. Late occurrences have been reported with sirolimus, but are very rare with everolimus. However, it is still important to always consider everolimus-associated pneumonitis in a differential diagnosis of pulmonary symptoms. This follows the recent, well-documented, but albeit rare case report of everolimus-associated pneumonitis 5 years after the initiation of everolimus therapy (Velioglu et al. 2018).

A significant number of studies are exploring the use of mTOR inhibitors as CNI-sparing agents (De Simone et al., 2012). mTOR inhibitors reduce the renal impact of CNI agents by enabling reduced doses of CNIs to be used. Cytokine suppression is key to the success of CNIs and a study was set up to investigate the effect of everolimus versus mycophenolic acid (MPA) on the transcription of several cytokines (Iwasaki et al., 2019).

Peripheral blood mononuclear cells obtained from healthy volunteers were stimulated with anti-CD3/28 microbeads in the presence of ciclosporin A (CSA), tacrolimus (TAC), everolimus (EVR), and/or mycophenolic acid (MPA) for 8 hours. The mRNA levels of each cytokine were then measured using quantitative real-time polymerase chain reaction.

MPA had no inhibitory effect on any of the cytokines tested. EVR showed moderate inhibition of IL-2, IL-10, IL-21, and IFNγ levels. The beneficial effect of EVR addition was present at low concentrations of CSA or TAC and was not increased at higher concentrations of CSA or TAC.

The results suggest that everolimus inhibits activation of the immune response, specifically cytokines, in transplant recipients. Everolimus was effective at even low doses of CNIs, thereby enabling the adverse effects of CNIs to be alleviated while still providing protection against graft rejection (Iwasaki et al., 2019).

A recent study has shown that post-transplant patients have a lower incidence of malignancy when treated with mTOR inhibitors, whether used with CNIs or not. The beneficial effects remain significant even when non-melanoma skin cancer are excluded (Wolf et al., 2018). 

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