Everolimus and sirolimus in transplantation-related but different

Abstract

Introduction: The inhibitors of the mammalian target of rapamycin (mTOR) sirolimus and everolimus are used not only as immunosuppressants after organ transplantation in combination with calcineurin inhibitors (CNIs) but also as proliferation signal inhibitors coated on drug-eluting stents and in cancer therapy. Notwithstanding their related chemical structures, both have distinct pharmacokinetic, pharmacodynamic and toxicodynamic properties.

Areas covered: The additional hydroxyethyl group at the C(40) of the everolimus molecule results in different tissue and subcellular distribution, different affinities to active drug transporters and drug-metabolizing enzymes as well as differences in drug-target protein interactions including a much higher potency in terms of interacting with the mTOR complex 2 than sirolimus. Said mechanistic differences as well as differences found in clinical trials in transplant patients are reviewed.

Expert opinion: In comparison to sirolimus, everolimus has higher bioavailability, a shorter terminal half-life, different blood metabolite patterns, the potential to antagonize the negative effects of CNIs on neuronal and kidney cell metabolism (which sirolimus enhances), the ability to stimulate mitochondrial oxidation (which sirolimus inhibits) and to reduce vascular inflammation to a greater extent. A head-to-head, randomized trial comparing the safety and tolerability of these two mTOR inhibitors in solid organ transplant recipients is merited.

Keywords: comparison; drug metabolism; everolimus; mammalian target of rapamycin complex 2; mitochondria; nephrotoxicity; neuronal metabolism; pharmacokinetics; sirolimus; vascular inflammation.

Figure 1. Chemical structures of everolimus and sirolimus

Numbering of the molecule follows the IUPAC nomenclature [14]. Regions of the macrolide ring binding to mTOR and FK-binding proteins, the so-called mTOR binding domain and FK-binding protein (FKPB)- binding domain [15], are marked.

Figure 2. Distinct effects of everolimus and sirolimus on the mTOR pathway

The figure is based on data from [15,22,23,26]. The serine–threonine kinase mTOR plays a key role in, among others, the regulation of cell proliferation, cell metabolism (including glycolysis) and protein synthesis. It forms two complexes: mTORC1 and mTORC2. Sirolimus and everolimus bind to FKBP12 [15] and then this complex inhibits activation of mTORC1 by dissociating Raptor from mTORC1. mTORC2 is not inhibited directly by the sirolimus/FKBP-12 complex. Nevertheless, but prolonged sirolimus treatment may reduce mTORC2 activity. However, as shown in [26], everolimus is markedly more potent than sirolimus in inhibiting mTORC2 formation. Everolimus effectively targets mTORC2-dependent signaling and ERK1/2 activation, an effect that sirolimus is lacking. ERK1 and ERK2 are serine/threonine kinases that are involved in cell proliferation, differentiation, survival and reorganization of the actin cytoskeleton. A functional link between ERK and mTORC2 has been shown. Thus inhibition of ERK by everolimus may occur via mTORC2 [26]. Arrows and bars represent activation and inhibition, respectively. Please note that the mTOR pathway is greatly simplified. For more details and explanation of the acronyms, please see [23]. Abbreviations: EVL: everolimus, SRL: sirolimus.

Figure 3. Comparison of everolimus and sirolimus in vitro metabolism after incubation with human liver microsomes

Data is taken from [36]. To facilitate visual comparison error bars are not shown. Abbreviations: -OH: hydroxy everolimus or hydroxy sirolimus, -des: desmethyl everolimus or desmethyl sirolimus, OH-piper: hydroxy piperidine everolimus or hydroxy piperidine sirolimus. The exact hydroxylation positions at the piperidine ring could not be identified, however, different high-performance liquid chromatography retention times suggested hydroxylation at different positions (hydroxy piperidine I and II).

Figure 4. Comparison of the effects of sirolimus (SRL) and everolimus (EVL) in combination with cyclosporine (CsA, 10 mg/kg/day) on the proximal tubule kidney injury marker trimethylamine oxide (TMAO) in rat urine after 28 days of exposure as assessed using ¹H-magnetic resonance spectroscopy (MRS)

Data is taken from references [36,60]. Values were normalized based on the total spectrum integral to compensate for differences in urine concentrations. Thus, all values are per mille of the total integral and are reported as means ± standard deviations (n=4). Data among groups was compared using analysis of variance in combination with Tukey’s post-hoc test. Not all statistically significant differences are shown to facilitate visual comparison of the data. The numbers in the treatment axis labels give the doses in mg/kg/day. All immunosuppressants were administered by oral gavage resulting in whole blood concentrations within the target range of transplant patients [36,60].