Table 4.

Key toxicity profiles and adverse events

Study	Key adverse events
Gundermann et al. [28] Activation of mTORC1 signaling and protein synthesis in human muscle following blood flow restriction exercise is inhibited by rapamycin	No issues raised - Study takes place over a short period and in healthy, young volunteers
Dickinson et al. [29] Mammalian target of rapamycin complex 1 activation is required for the stimulation of human skeletal muscle protein synthesis by essential amino acids	No issues raised - Study takes place over a short period and in healthy, young volunteers
Dickinson et al. [30] Rapamycin does not affect post-absorptive protein metabolism in human skeletal muscle	No issues raised - Study takes place over a short period and in healthy, young volunteers
Drummond et al. [31] Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis	No issues raised - Study takes place over a short period and in healthy, young volunteers
Veasey-Rodrigues et al. [32] A pilot study of Temsirolimus and body composition	Toxicity data—Study listed most common toxicities that were, at least possibly, drug-related. These were grouped into 2 groups: grade 1–2 and grade 3–4, based on the Common Terminology Criteria for Adverse Events version 3.0 Grade 1–2 - Fatigue (100%) - Anaemia (100%) - Hyperglycaemia (81%) - Hypercholesterolemia (75%) Grade 3–4: - Anaemia - Thrombocytopenia - Leukopenia/neutropenia - Aspartate aminotransferase/alanine aminotransferase elevations The study did not correlate baseline sarcopenia with a toxicity profile - Median number of toxicities per patient was 7 between sarcopenic and non-sarcopenic participants Study noted no significant difference between toxicities in participants and their baseline body composition
Gyawali et al. [33] Muscle wasting associated with the long-term use of mTOR inhibitors	The Time to treatment failure (TTF) was another outcome measured in the study. The author explains its definition as the time between starting the mTOR inhibitor to when it is stopped The author lists reasons for stopping as adverse events, disease progression, or mortality - However, there currently is no further detail into the reasons for the participants stopping treatment TTF was noted not to be associated with the sarcopenic status of patients
Campistol et al. [23] Bone metabolism in renal transplant patients treated with cyclosporine or sirolimus	Safety information was obtained from individual studies analyzed by Campistol et al Study 1 Participants that discontinued the study due to several reasons. Notable ones possibly relating to the use of the mTOR inhibitor include:  Leukopenia - Thrombocytopenia - Hypercholesterolemia/hyperlipidaemia - Increased liver enzymes Key adverse events (sirolimus vs cyclosporin A) - Hypertriglyceridemia (51% vs 12%, P < 0.01) - Hypercholesterolemia (44% vs 14%, P < 0.01) - Hyperglycaemia (20% vs 7%) - Insulin dependent diabetes (2% vs 2%) - SGOT (aspartate aminotransferase) elevation (17% vs 0, P < 0.05) - Hypokalaemia (34% vs 0, P < 0.01) - Hypophosphatasaemia (15% vs 0, P < 0.05) - Thrombocytopenia (37% vs 0, P < 0.01) - Leukopenia (39% vs 14%, P < 0.05) - Anaemia (37% vs 24%) - Arthralgia (20% vs 0, P < 0.05) - Pneumonia (17% vs 2%, P < 0.05) Sirolimus group also experienced a higher number of infections, but numbers were still similar (n = 25 vs n = 22) Study 2 Some discontinuations of participants in the sirolimus group were due to agranulocytosis and hyperlipidaemia Key adverse events (sirolimus vs cyclosporin A) - Hypertriglyceridemia (73% vs 50%) - Hypercholesterolemia (65% vs 45%) - Hyperglycaemia (15% vs 16%) - Insulin dependent diabetes (3% vs 3%) - SGOT (aspartate aminotransferase) elevation (13% vs 5%) - Creatinine increase (18% vs 39%, P < 0.05) - Hyperuricemia (3% vs 18%, P < 0.05) - Thrombocytopenia (45% vs 8%, P < 0.01) - Leukopenia (28% vs 18%) - Anaemia (43% vs 29%) - Diarrhoea (38% vs 11%, P < 0.01)
Westenfeld et al. [24] Impact of sirolimus, tacrolimus and mycophenolate mofetil on osteoclastogenesis—implications for post-transplantation bone disease	Key metabolic effects in sirolimus vs calcineurin inhibitor - Cholesterol (Elevated, P = 0.001) - Triglycerides (Elevated, P = 0.002) - Haemoglobin (Decreased, P = 0.048) - Intact parathyroid hormone (Elevated, P = 0.032) Study explained no change in platelets or leucocyte count between groups
Sessa et al. [25] Immunosuppressive agents and bone disease in renal transplant patients with hypercalcemia	No information
Gnant et al. [26] Effect of Everolimus on Bone Marker Levels and Progressive Disease in Bone in BOLERO-2	Safety information obtained from poster used in San Antonio Breast Cancer Symposium, as referenced by Gnant et al Study graded adverse events from 1 to 4 Key adverse events at all grades (everolimus vs placebo) - Hyperglycaemia (14% vs 1%) - Pneumonitis (16% vs 0) - Stomatitis (59% vs 12%) - Rash (39% vs 7%) - Fatigue (37% vs 27%) - Diarrhoea (34% vs 19%) - Nausea (31% vs 29%) - Decreased weight (28% vs 7%) Most common grade 3–4 adverse events (everolimus vs placebo) - Stomatitis (8% vs < 1%) - Hyperglycaemia (5% vs < 1%) - Fatigue (4% vs 1%) Bone-related adverse events were reported to be low and similar across treatment arms, though fewer fractures were reported in the everolimus arm (2.3% vs 3.8%) The population in the everolimus arm was twice that in the placebo arm (n = 428 vs n = 238)
Hadji et al. [27] The impact of mammalian target of rapamycin inhibition on bone health in postmenopausal women with hormone receptor-positive advanced breast cancer receiving everolimus plus exemestane in the phase IIIb 4EVER trial	In the study, 24.7% of discontinuations were due to adverse events. 53.7% of patients required at least one dose reduction of everolimus Key common adverse events in safety population (all grades, grade 3–4) - Stomatitis (49.2%, 8.4%) - Fatigue (36.1%, 3.3%) - Diarrhoea (26.4%, 2%) - Nausea (26.1%, 3%) - Rash (22.7%, 1%) - Anaemia (17.7%, 4.3%) - Thrombocytopenia (7.7%, 1.7%) - Hyperglycaemia (5%, 1.3%) Skeletal adverse events - Fracture (2.7%) - Osteonecrosis of the jaw (0.7%) - Osteoporosis (0.3%)
Bryun et al. [34] Everolimus in patients with rheumatoid arthritis receiving concomitant methotrexate: a 3-month, double-blind, randomized, placebo-controlled, parallel-group, proof-of-concept study	88.5% of the everolimus arm population reported adverse events compared to the 70% reported in the placebo arm Slightly more participants in the everolimus arm discontinued due to adverse (10 vs 6) Key drug-related adverse events at 12 weeks (everolimus vs placebo) - Gastrointestinal disorders (31.1% vs 10%) - Skin/subcutaneous disorders (16.4% vs 1.7%) - Infections/infestations (9.8% vs 1.7%) - Hypercholesterolemia (6.6% vs 1.7%) An increase in lipids was noted in the everolimus group to be statistically significant but returned to baseline at the end of the treatment. More of the everolimus population had exceeded the upper limit in tests compared to the placebo Leucocyte/neutrophil count was decreased significantly in the everolimus group at week 12 from baseline but returned to baseline by 24 weeks Platelets were also decreased, but the difference was not significant The study mentions that liver markers (AST, ALT, alkaline phosphatase) were raised in the everolimus arm but not considered clinically meaningful
Wen et al. [35] Low-dose sirolimus immunoregulation therapy in patients with active rheumatoid arthritis: a 24-week follow-up of the randomized, open-label, parallel-controlled trial	One patient was known to have discontinued study due to lower limb oedema, attributed to sirolimus intolerance Key safety outcomes - Red blood cell counts and haemoglobin concentration had no significant changes compared to control (P > 0.05) - Platelet count was significantly higher in sirolimus arm at one time point (3 weeks) but insignificant at others - Neutrophilic granulocyte levels were lower compared to baseline at weeks 3 and 12 (P < 0.05) - Liver function markers were not affected - Renal function was not affected No cases of thrombocytopenia, mucositis, or proteinuria were observed
Niu et al. [36] Sirolimus selectively increases circulating Treg cell numbers and restores the Th17/Treg balance in rheumatoid arthritis patients with low disease activity or in DAS28 remission who previously received conventional disease-modifying anti-rheumatic drugs	Study explains no serious adverse events occurred during the study Minor adverse events include - Rash - Oral ulcers - Alopecia These side effects occurred in 3 participants and did not require special care