I emailed several of the original authors (including lead), reaching out to give us some further insight…
I received one hit back at time of writing, see attached back/forth exchange.
Sirolimus-GFJ Study- M Ratain Comments.pdf (33.4 KB)
One notable comment:
“I will add that I have serious reservations about the use of Sirolimus for general prophylactic purposes, since the drug can cause both serious interstitial lung disease, as well as anemia due to impaired iron utilization”.
Has Dr Green given this adverse effect warning?
Also, on elevated glucose and lipids…“that’s how you know it’s working”. I’ve not even reached this state yet, so I have runway.
He provided no references to the lung disease assertion/context other than I assume his clinical practice. I donate blood every 8 weeks to expressly dump iron, whilst taking Rapamycin, and have zero side effects to date. I would be classified as iron deficient without anemia (self-induced), although my hemoglobin is normal. (But I’m also homozygous H63D…so maybe I have deep cellular iron storage reserves not captured in blood tests)
Regarding Interstitial Lung Disease (ILD) and mTOR inhibitors:
“In February 2017, after completion of chemotherapy she was started on Sirolimus 2mg daily. The level was maintained at 5–10 ng/ml. In July 2017, the patient presented with dry cough, fever and dyspnea on exertion for six weeks. In November 2017, sirolimus was discontinued and she was switched to everolimus at 0.75 mg twice daily. The level was maintained at 4–8 ng/ml. Within one week the patient experienced improvement in her symptoms and she was back to her baseline level of activity after two months”
Here’s another:
“The literature review identified 57 publications on ILD in solid organ TxR receiving everolimus or sirolimus. ILD presented months or years after mTORi initiation and symptoms were nonspecific and insidious. The event was more frequent in patients with a late switch to mTORi. In most cases, ILD was reversed after prompt mTORi discontinuation. ILD induced by mTORi is an uncommon and potentially fatal event warranting early recognition and drug discontinuation. Out of the 1,473 de novo TxR receiving everolimus in Phase III trials, everolimus-related ILD was confirmed in six cases (one kidney, four heart, and one liver TxR) representing an incidence of 0.4%”
ILD wasn’t even a noted adverse event in the Sirolimus/GFJ trial, only anemia (DLT in only 5 of 138 persons)? It appears to be something associated with chronic daily Sirolimus administration and some significant length of time (malignant cancer/transplant setting), you can feel it coming on, and thus, backing off dosing, reversible.
I am not perturbed in an intermittent dose model. As long as you closely monitor blood markers and side effects, whenever it reaches tolerance levels, you just back off. The effects of Rapamycin are reversible, hundreds of studies have shown this.
You’ve said “20mg, which for us is way high”, and “max increases 3.5X, then that’s a lot (equal to 28mg”. Define high and a lot?
Unless you do your own n=1 experiment, monitoring blood markers and side effects, you just don’t know your limit, whatever that target might be for YOU. We don’t even know what level of mTOR suppression in humans reaches high percentile to flatten the aging curve?The GFJ study gives some insight for cancer target (and it’s higher than what most of us take)…is this “the” target for longevity?
Genetic predisposition to CYP3A4 enzyme polymorphisms/expression, mTOR polymorphisms, GFJ type/dose, gastric processing, base levels of nutrient signalling, timing, etc will all have major impacts on your personal pharmacokinetics/response. Different cell lines/organs have varying degrees of mTOR suppression.
GFJ/drug interaction is highly specific. GFJ can have a HUGE impact on some statins.
“In a randomized cross-over study with two phases, 10 healthy volunteers ingested grapefruit juice 200 ml or water (control) for 3 days. On day 3, a single 40-mg dose of simvastatin was administered with grapefruit juice 200 ml or water. Plasma concentrations of simvastatin and simvastatin acid were determined up to 24 h. Grapefruit juice increased the area under the plasma concentration–time curves from 0 to 24 h [AUC(0–24)] of simvastatin 3.6-fold and that of simvastatin acid 3.3-fold (range 2.1–5.6-fold; respectively. The peak concentrations (Cmax) of simvastatin and simvastatin acid were increased 3.9-fold and 4.3-fold (range 2.7–7.9-fold;
by grapefruit juice.”
“This crossover study consisted of 5 study days, during which 10 healthy volunteers ingested 40
mg simvastatin with water (control), with “high-dose” grapefruit juice (200 mL double-strength grapefruit juice three times a day for 3 days), or 1, 3, and 7 days after ingestion of “high-dose” grapefruit juice. For safety reasons, the study was performed in three parts to allow simvastatin-free days between the study days. Serum concentrations of simvastatin and simvastatin acid were measured by liquid chromatography–tandem mass spectrometry up to 12 hours. When simvastatin was taken with grapefruit juice, the mean peak serum concentration (Cmax) and the mean area under the serum concentration-time curve [AUC(0-∞)] of simvastatin were increased 12.0-fold (P < .001) and 13.5-fold (P < .001), respectively, compared with control. When simvastatin was
administered 24 hours after ingestion of the last dose of grapefruit juice, the Cmax and AUC(0-∞) were increased 2.4-fold (P < .01) and 2.1-fold (P < .001), respectively, compared with control. When simvastatin was given 3 days after ingestion of grapefruit juice, the Cmax and AUC(0-∞) were increased 1.5- fold (P = .12) and 1.4-fold (P = .09), respectively, compared with control”
“In a randomized, four-phase crossover study, eight healthy subjects consumed either GFJ or water t.i.d. for 4 days in each trial. On each final day, a single dose of 4 mg pitavastatin or 20 mg atorvastatin was administered. GFJ increased the mean AUC 0-24 of atorvastatin acid by 83% (95% CI 23–144%)and that of pitavastatin acid by 13% (-3 to 29%).”
“We determined the validity of current medical advice to avoid grapefruit juice consumption while taking 3 widely used statins. A daily glass of grapefruit juice increases blood levels of simvastatin and lovastatin by about 260% if taken at the same time (about 90% if taken 12 hours apart), and atorvastatin by about 80% (whenever taken). Simvastatin 40 mg, lovastatin 40 mg, and atorvastatin 10 mg daily reduce low-density lipoprotein (LDL) cholesterol levels in a 60-year-old man with an LDL cholesterol of 4.8 mmol/L by 37%, reducing ischemic heart disease risk by 61%. When simvastatin or lovastatin are taken at the same time as grapefruit juice, the estimated reduction in LDL cholesterol is 48%, and in heart disease is 70%. If the juice is taken 12 hours before these statins, the reductions are, respectively, 43% and 66%, and for atorvastatin, 42% and 66%. The increased rhabdomyolysis risk from grapefruit juice consumption due to the increased effective statin dose is minimal compared with the greater effect in preventing heart disease. Grapefruit juice should not be contraindicated in people taking statins.”
