Tuesday, 25 April 2017

Sildenafil during Chemo

PDE5 inhibitors have been studied some and discussed by the group in regards to both the short term potential for BBB opening and thus allowing higher doses of chemo drugs into tumors, and also for their impact on immune suppressor cell regulation with longer term supplementation.

I've been trying understand the applicability of Sildenafil specifically for low grade tumors which inherently have minimally if any disruption of the blood brain barrier.  

I have not been able to find much more than a few decent studies. 2 of them are one AstrocytomaOptions:
https://www.ncbi.nlm.nih.gov/pubmed/21610107
https://www.ncbi.nlm.nih.gov/pubmed/21402712
and one other good one I found was:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2632551/

Here on btcoctails its referenced in the range of 20-40mg total dose per day, but this and a few other studies showed 50mg per kg dosing in rat models which is maybe 500x higher.  But I haven't found plasma concentration info to actually map it to human dosing.  The closest I found was pharmocokinetic comparisons listing equivalent half lives between rat and human and coming up with the half life for humans being about 4x longer than in rats.  That was useful because it indicates that dose timing should be stretched out to match Tmax of sildenafil with Tmax of chemo.  But actual dosage that would be sensible and safe I haven't been able to figure out.

So does anyone have input on tying it with an actual chemo rounds or recommendations on a sensible dosage?

Thanks!
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8 comments:

  1. Stephen W25 April 2017 at 17:36

    The only way to accurately translate rodent doses to human doses would be to do an actual pharmacokinetic study in the rodents and measure their blood directly for levels of the drug. Any other way of calculating it is only a very rough approximation. I've given up trying to translate rodent doses into human doses. Rodent metabolism might also be very different from human metabolism leading to a different profile of drug metabolites in rodents compared to humans. Also rodents are often injected with drugs, usually intraperitoneally, that are taken by humans orally, giving much higher peak plasma concentrations than humans would get.

    I've also come to have a somewhat different view of sildenafil following the publication of a recent study:
    http://btcocktails.blogspot.ca/2017/01/re-evaluating-sildenafil-viagra-in-gbm.html

    The only way to really establish a proper human dose for use in blood-brain barrier disruption is through human trials, of which at least one is underway
    https://clinicaltrials.gov/ct2/show/NCT01817751

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    Replies
    1. Stephen W25 April 2017 at 17:44

      In mice, a single oral dose of 10mg/kg sildenafil can give a Cmax of around 200 micrograms per liter (~420 nanomolar). Compare this with a Cmax of 335 nanomolar after a single oral dose of 50 mg in humans. But of course the time to clear the drug from the bloodstream will likely be quicker in mice, leading to a shorter exposure.

      https://www.ncbi.nlm.nih.gov/pubmed/10219969

      Plasma protein binding of the drug might also be quite different in mice versus humans, which affects the amount of active, free drug.

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    2. bs196625 April 2017 at 19:30

      Thanks Stephen!

      I had read your noted post in regards to sildenafil and GBM, but didn't think it applied as much in this case since it would be a few single dose instances and not long term treatment.

      The Cmax reference though is great info, though a bit puzzling. Seems surprising that 10mg/kg in a rat vs 50mg per a roughly 70kg human, so 0.7mg/kg human would produce fairly similar Cmax values. I guess not unreasonable though given the typical estimate of 7x metabolic rate difference between rat and human.

      It would be a nice result though since 50mg is a fairly standard dose of sildenafil for typical E.D. issues. So would in no way be a dangerous dose level. Most references I saw indicated less than a 10% drop in blood pressure for patients treated at 50mg.

      The clinical trials will of course be more informative, but until they publish something it doesn't do much good :(

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    3. Stephen W25 April 2017 at 19:39

      The standard allometric scaling conversion between mouse and human is to multiply the mouse dose in mg/kg by 0.08 to get the approximate human dose in mg/kg.

      In this case 10 x 0.08 = 0.8.

      0.8 mg x 70 kg human = 56 mg

      So the conversion works pretty well in this case.

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    4. Stephen W25 April 2017 at 19:45

      I think the conversion between rat and human (mg/kg -> mg/kg) is about 0.16, as opposed to 0.08 for mice.

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    5. bs196628 April 2017 at 17:10

      Ok that makes sense.

      One thing I was seeing from pharmacodynamics link you posted was the abstract says tmax was similar in all species, except in rats. I can't open the full article, can you? Does it give an actual tmax for rats? The reason is that the BBB studies show fairly narrow windows of effectiveness and so I wanted understand the comparisons of human vs rat tmax values.

      Thanks!

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    6. Stephen W28 April 2017 at 20:00

      To get articles behind paywalls for free:

      Follow the link in pubmed to the "Full text links" which will take you the journal where the study was published.

      Keep on clicking the links until you hit the paywall. In this case, click "Get access". Now you've reached the paywall.

      Now copy the URL of that page and go to sci-hub.cc

      Paste the URL into the search box at sci-hub

      The study is now yours for free.

      http://www.tandfonline.com.sci-hub.cc/doi/pdf/10.1080/004982599238687?needAccess=true

      Delete
    7. bs19661 May 2017 at 13:33

      WOAH! That is fantastic! I had been bugging academic friends to use their university accounts to get me access to papers from time to time, but sci-hub is the bomb!

      Thanks!

      Delete

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