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Why people taking same dose of Rapamycin have different blood Rapamycin concentrations?

Image credit: https://www.cellsignal.com/products/activators-inhibitors/rapamycin/9904

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Shubhankar Kulkarni
Shubhankar Kulkarni Aug 05, 2020
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Necessity

Is the problem still unsolved?

Conciseness

Is it concisely described?

Mikhail Blagosklonny mentioned in his paper "Rapamycin for longevity: an opinion article" that "Blood levels of rapamycin should be measured, as the rapamycin concentration in the blood varies greatly among individuals taking the same dose."

Also, does this happen with every other drug we consume?

[1]Blagosklonny M V. Rapamycin for longevity: opinion article. Aging (Albany NY) [Internet]. 2019 Oct 4;11(19):8048–67. Available from: http://www.aging-us.com/article/102355/text

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Creative contributions

Certain disorders can impact the rapamycin concentration

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Juran Dec 12, 2020
Due to the administration of rapamycin by taking the Rapamune (Pfizer) pills or solution orally, rapamycin must be absorbed by cells in the gastrointestinal tract. When inside, rapamycin is being metabolized by the CYP3A4 and P-gp, both increasingly represented in the intestine and liver . Therefore, any metabolic or metabolism-affecting disorder could affect the rapamycin concentration.

The most known to affect drug metabolism generally is hepatic impairment. It was shown that when compared to healthy patients, those having severe Child-Pugh class A/B hepatic impairment had proportionally longer rapamycin half-life and AUC . On the other hand, renal disorders showed not to have a significant impact on rapamycin blood concentrations.

Therefore, comparing patients, without knowing if they have active disease or impairment that could affect rapamycin blood concentration, shouldn't be taken for granted.

Do you know any other disease strongly affecting rapamycin or a similar drug?


[1]Stenton, S. B., Partovi, N., & Ensom, M. H. H. (2005). Sirolimus. Clinical Pharmacokinetics, 44(8), 769–786. doi:10.2165/00003088-200544080-00001

[2]https://www.rxlist.com/slideshow_pictures_high_blood_pressure/article.htm

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Interactions with other drugs can influence the rapamycin pharmacokinetics

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Juran Dec 12, 2020
Rapamycin (Sirolimus) concentrations are known to vary a lot between the patients, and it can be due to drug interactions. As Rapamycin is metabolized by CYP3A4 and P-gp, any drug affecting these enzymes/proteins can alter the drug metabolism. Since both enzymes inactivate and export rapamycin out of the cells, thus decreasing its concentration, we can define the drugs affecting these enzymes as:
  • Enhancers – drugs that inhibit CYP3A4 and/or P-gp and increase the concentration/half-time of rapamycin
  • Diminishers – drugs that induce the activity of the enzymes and decrease the rapamycin concentration/shorten the half-time
Enhancers (inhibitors of the enzymes)
  • Cyclosporine – the best known rapamycin-interacting drug, which is an inhibitor of both CYP3A4 and P-gp. If this interaction is unwanted, it can be diminished by the administration of rapamycin at least four hours after the cyclosporine.
  • Diltiazem – inhibiting both enzymes; simultaneous administration of diltiazem and rapamycin increased rapamycin concentrations 1.4-1.6-fold.
  • Ketoconazole – inhibiting both enzymes; co-administration resulted in 4.2-fold Cmax and 38% half-time rapamycin increase; co-administration not recommended
  • Voriconazole, Itraconazole, Fluconazole
  • Erythromycin – inhibiting both enzymes; simultaneous administration with rapamycin increased the concentration of rapamycin and erythromycin by 4.4-fold and 1.7-fold, respectively.
  • Telithromycin, Clarithromycin
  • Verapamil – an inhibitor of both enzymes; co-administration increased rapamycin Cmax and AUC by 2.3- and 2.2-fold, respectively.
  • Bromocriptine, cimetidine, cisapride, clotrimazole, danazol, protease inhibitors, and others
  • Grapefruit juice (furanocoumarins and flavonoids competing for the CYP3A4 )

Diminishers (inducers of the enzymes)
  • Rifampin – inducer of both enzymes; co-administration of 600 mg of rifampin with 20 mg of rapamycin reduced AUC 82% and Cmax 71%.
  • Carbamazepine, phenobarbital, phenytoin, rifapentine
  • St. John's Wort (Hypericum perforatum) - induction of the cytochrome P450 enzymes CYP3A4 and CYP1A2
In conclusion, patient's recent history or the ongoing drug administration must be taken into consideration before comparing the rapamycin blood concentrations.

[1]Stenton, S. B., Partovi, N., & Ensom, M. H. H. (2005). Sirolimus. Clinical Pharmacokinetics, 44(8), 769–786. doi:10.2165/00003088-200544080-00001

[2]https://link.springer.com/article/10.2165%2F00002018-199818040-00002

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It matters if your stomache is full or not

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Juran Dec 12, 2020
As described in the product description, Rapamune® from Pfizer (rapamycin) can be administered in two ways (mentioned in other contributions), with or without food . So, does it matter if you just ate or you have been fasting for 24 hours?

The metabolism differences between healthy patients are widely known and they must be taken into account by the pharma industry when producing drugs. The area which describes the dynamics of drug metabolism is called pharmacokinetics.

To explain it better, scientists have shown that a healthy patient consuming a high-fat meal (861.8 kcal, 54.9% kcal from fat) had increased mean total exposure (AUC) of rapamycin by 23 to 35%, compared with a patient who fasted. The observed differences are even more dramatic in patients with metabolic or metabolism-affecting disorders. Also, other data on the effects of food on rapamycin metabolism were generally inconsistent .

Because of all the above mentioned, pharmaceutical companies do not tend to fight this problem and consequently, we should not compare the concentrations of patients receiving rapamycin therapy.

Pharma recommends consistency of the therapy and continuous monitoring of the rapamycin concentration. In other words, you should find a way how you will plan your meals along with therapy and stick to the plan. Once you found a suitable diet & therapy regime resulting in ideal rapamycin concentrations, don't change it!

[1]https://www.rxlist.com/rapamune-drug.htm#clinpharm

[2]Stenton, S. B., Partovi, N., & Ensom, M. H. H. (2005). Sirolimus. Clinical Pharmacokinetics, 44(8), 769–786. doi:10.2165/00003088-200544080-00001

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Blood concentration of rapamycin depends on blood composition

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Juran Dec 12, 2020
Scientists have shown that rapamycin is extensively „lost“ in blood. The astonishing 92% of rapamycin is being strongly bound by human plasma proteins such as albumin, α1-acid glycoprotein, and lipoproteins . Therefore, any difference in blood composition can influence the (blood) concentration of rapamycin.

[1]https://www.rxlist.com/rapamune-drug.htm#clinpharm

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Differences in rapamycin concentrations caused by the administration types of Rapamune

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Juran Dec 12, 2020
It also depends on how rapamycin is used. It can be administered as an oral 2 mg/ml solution or a triangle-shaped pill of 0.5, 1, and 2 mg (Rapamune®, Pfizer).

Data shows that the bioavailability after the administration of rapamycin pill is 27% higher than that of rapamycin oral solution of an equal dose. Although there is some evidence that clinical equivalence of both administration types was shown at 2 mg dose, bioavailability data shows that consistency of administration type is always recommended to avoid dosage differences .

To conclude, any cross-patient comparisons should consider the administration form, too.

[1]https://www.rxlist.com/rapamune-drug.htm#clinpharm

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Different concentration-measuring techniques yielding different results

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Juran Dec 12, 2020
When inside the body, most of the rapamycin is being absorbed on plasma proteins in the blood. Therefore, the best concentration measurement compartment for rapamycin is the blood. Patient blood is taken by the specialist and stored in EDTA tubes. Samples are stable for 24h up to 3 months, depending on the storage temperature . Its concentration is usually being measured by:
  • High-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS)
  • High-performance liquid chromatography with ultraviolet detection (LC-UV)
  • Radioreceptor assay (RRA) aka Immunophilin-binding assay
  • Microparticle enzyme immunoassay (MEIA)
Comparing the measurements, blood concentrations of rapamycin shown that LC-MS/MS and LC-UV show very similar results (SD 20%). Compared to LS-UV, RRA showed significantly higher results, while the highest overestimations have been reported by using MEIA (unspecific binding to sirolimus metabolites). Generally, experiments showed that chromatographic methods such as LC-MS/MS and LC-UV result in 20% lower concentration measurements than MEIA (on average) .

Nowadays, there are some new techniques (or upgrades of the old ones), that can result in different rapamycin concentration measurements, such as: Elecsys® Everolimus and Sirolimus electrochemiluminescence immunoassays , chemiluminescent magnetic microparticle immunoassay (CMIA) and others.

Therefore, storing protocols, time passed from the sampling to measurement, and the type of measurement used can influence rapamycin concentration and account for a certain percentage of observed cross-patient differences.

[1]Stenton, S. B., Partovi, N., & Ensom, M. H. H. (2005). Sirolimus. Clinical Pharmacokinetics, 44(8), 769–786. doi:10.2165/00003088-200544080-00001

[2]MacDonald A, Scarola J, Burke JT, Zimmerman JJ. Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus. Clin Ther. 2000;22 Suppl B:B101-121. doi: 10.1016/s0149-2918(00)89027-x. PMID: 10823378.

[3]Lee EJ, Kim HK, Ahn S, Lee W, Kim HS, Chun S, Min WK. Accuracy evaluation of automated electrochemiluminescence immunoassay for everolimus and sirolimus compared to liquid chromatography-tandem mass spectrometry. J Clin Lab Anal. 2019 Sep;33(7):e22941. doi: 10.1002/jcla.22941. Epub 2019 Jun 14. PMID: 31197901; PMCID: PMC6757180

[4]https://www.sciencedirect.com/science/article/abs/pii/S0009912009002768

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General comments

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Darko Savic
Darko Savica year ago
I would imagine that this is the case with every substance we consume. I look at the human body as one large bioreactor with countless simultaneous chemical reactions continuously taking place since the zygote stage. Even though development follows a "recipe", the product is somewhat unique because it came from so many variables. Everyone is a differently built bioreactor that came from roughly the same plan but made by different crews in different environments :)
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