Wary of, interested in, or using Afrezza? You should read this

I'm off to the endo today at 3:40p to start my Afrezza odyssey. In preparation, I've done a PhD dissertation of research in the last few days.

I've started this discussion to cover scientific aspects of the drug, so that people can find some of the same peace and confidence I have gained in the last few days from learning details about how it actually works on the cellular/molecular level, and how well it's working from anecdotal testimony.

This is not MY thread. Please, anyone with scientific information to add, please do.

First readers: Please be patient... First point of information coming in the first reply.

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NOt that this is new information , but still wanted to post the links



Like many, I was concerned about just what exactly was happening in my lungs when Afrezza is put into it. I'm especially attuned to this question having followed some injectible "ultrafast" insulins being developed, and the biochemical techniques used to speed absorption.

The way that stuff works scares me when lung tissue is in play.

Fantastic news about Afrezza: The "magic" is nothing more exotic than a purely passive, non-chemical approach. Further the carrier, Technosphere (Mannind's invention) is composed of only N, O, and H in a very simple molecule, fumaryl diketopiperazine (FDKP -- name sounds scary, but then so is dihydrogen oxide if you don't know that that's H2O). The key is the mechanical folding of the molecule, which makes it fairly porous. Insulin sticks to it, but Technospheres generally don't like to stick to each other, so they don't clump and are easily dispersed into an atomized cloud.

Afrezza gets it's remarkable pharmacokinetic action simply by maximizing the spread of insulin over the entire alveolar surface area evenly. This allows for a very large immediate flux (flow rate) of insulin molecules across the type I pneumocytes enclosing an alveolus.

What happens to the FDKP molecule post-administration I'm still researching. However, according the literature available that I've found so far, it is not metabolically involved at all, so I'm guessing right now that it simply breaks down into water and Nitrogen gas, and is absorbed without issue.

So, what is an Afrezza particle? A tiny little sponge made from a loosely folded up FDKP molecule, soaked with Humulin. That's it.

The remarkable behavior of Afrezza is due entirely to how it effects the distribution of the insulin-bearing particles so that they provide the maximum exposure of the lung surface to the insulin when inhaled.

Some numbers and illustrations to reference in thinking abou all this:

Technosphere diameter: 2µ (microns -- millionth of a meter)
Alveolus diameter: 250µ ; inside surface area: 200,000µ2
Technosphere particles completely coating inside of alveolus: 50,000
Alveoli in typical lung: 70,000

Dave, this is about the best explanation I have seen for this process. Many have the question of the lung effect, rightfully so, but, you nailed it int about as elememtary as one could ask..Thank You. Too bad your statement couldnt be printed on the users label inserted with the product, huh?

Nice explanation, Dave! Keep them coming.


Still haven't yet been able to track down what happens to FDKP yet (I may just ping Mannkind... what the heck), but I did find this very detailed, researcher-speak poster on the Mannkind site that details data from a study looking at how fast insulin and FDKP clear after administration of Afrezza.

Check it out: http://www.mannkindcorp.com/collateral/documents/english-us/11-2009_easd_007-122_poster_955.pdf

Key takeaways I got from it: Only about half the inhaled powder makes it all the way to the surface of the alveoli! That throws another monkey wrench into the whole comparative "dosing" issue we've been been discussing so much...

Dave, good followup on FDKP from research. This tidbit alone may put many folks to ease on the question of dosing and dosing comparatives Afrezza with others(RAA).
just comfirms AM beliefs all along..Use it, and experience it for yourself, how better can anyone know results?

"So, what is an Afrezza particle? A tiny little sponge made from a loosely folded up FDKP molecule, soaked with Humulin."

The FDA can't put that on the label. People would understand it. :-)

Until I resolve what happens metabolically to clear FDKP, I'm a skosh more cautious than otherwise, but not enough to derail giving it a try.

I suppose for me after today it's gonna be, how soon can I get in and out of the pulmanologists office?

Dave - unreal man. Thanks for the explanation.

Dave, whats your background in chemistry?

I am getting worried that 30% of the insulin stays in the lungs 4+hours.

I wouldn't be concerned about this. It's insulin that still in the mucus lining the inner surface of the alveoli. As such, its OUTSIDE the cell cytoplasm, and therefore not acting on the metabolism of the pneumocytes. I suspect that a good portion of this get swallowed.

Because of this question, it got me thinking about another aspect of the initial administration that I'm researching and will report back on: What are the dynamics immediately after inhalation? Specifically, when the solid Technosphere contacts the wet inner surface, what exactly happens?

For example, if it comes in direct contact with the cell membrane and dissolves, I can see an initial higher spike of insulin diffusion as there is a high concentration right at the cell membrane, then as the dissolve insulin diffuses through the mucus and evens out in concentration, the flux falls off faster than with a simply half-life diffusion model.

In truth, though, I'm just speculating. All we do know is that that insulin doesn't seem to have any metabolic effect, which leads me to the conclusion it never crosses into the bloodstream, but is removed by the normal expulsion process going on all the time -- and we end up simply swallowing that stuff.

These illustrations helps give a better visualization of how it all fits together in an alveolus:

And one alveolus:

Chem 101 in college and... Renaissance Man :-)

Wow, Dave, this is intense, and I admit it's far above my level of understanding no matter how many times I read it. Other docs (not my Endo) have always told me that the 2 main things to watch out for with something like Afrezza is #1-lung cancer due to inhaling a growth hormone repeatedly into the lungs, but I honestly can't tell if it being within the alveoli surface yet outside of cell cytoplasm is a red flag or not. #2 pulmonary hypertention, and I would have no idea if this could ever cause high blood pressure within the lungs. To me it doesn't even seem that the post-marketing clinical trials are monitoring for this one at all...maybe with good reason since Pulmonologists were on the AdCom panel.
I am confused by where you say above that it doesn't cross into the bloodstream, are you saying that the insulin doesn't cross in the bloodstream OR the Technosphere doesn't? I'm certain that the insulin does.

I'm pretty sure that monkey wrench was already accounted for. I believe the units applied to the cartridges are unit equivalents, not the actual units of insulin in the package. The 10u in the clinical trials are now labeled 8u, but the cartridges still contain the same amount of Afrezza. They just adjusted the dose equivalence after studying how the stuff was performing in the trials.

I'm worried at the number of times I see folks getting samples from the docs without having the required lung testing being performed.

Dave, did you get the Afrezza from your endo in a sample pack or by RX? Did you have the lung testing first, and are you able to share the results of that??

Karen that’s what samples are for-- to let a patient try s limited qty without having to go to the headaches involved of getting a real rx. You won’t find any doctor who’s going to demand a PFT in order to get a free sample that’d be ridiculous. For a prescription a PFT is “indicated” but doctors would be well within their scope to forgo it as they see fit, or not…

Sam??? No doctor should obviously write the RX withhout following the prescribing recommendations which are clear regarding Lung Function Assessment Prior to Administration - AFREZZA is contraindicated in patients with chronic lung disease because of the risk of acute bronchospasm in these patients. Before initiating AFREZZA, perform a medical history, physical examination and spirometry (FEV1) in all patients to identify potential lung disease [see Contraindications (4) and Warnings and Precautions (5.1)].

This would apply to handing out samples as well. None of my docs even have "samples" in their closet to hand out to try. If folks are getting samples of a prescription drug in the office without proper testing and without the required RX, this is incredibly dangerous, not to mention unethical, and likely walking a legal line regarding dispensing.

I am going to take a deep breath and hope for the best for folks who don't have the lung function tests done at the very least.

I understand and have read the prescribing guidelines. But you are incorrect-- doctors frequently choose to follow or not follow exact prescribing guidelines, or to follow them to varying extents, and in this country we allow them the authority to do so-- they are just that, guidelines. If they followed every single guideline in the world that's all they'd be doing, following near infinite guidelines and not actually helping patients. Luckily we live in a country where the government doesn't dictate exactly how doctors must practice medicine.

As to doing spirometry before giving out a free sample... that is nowhere near reality at all. Very few doctors would ask a patient to undergo an expensive medical test of any kind in order to give them a free sample of anything, unless there are major indications that the patient shouldn't be taking that med to begin with and the doctor feels the need to document proof.

If doctors precisely followed prescribing guidelines--- about half the members of this board couldn't get injected insulin, pumps, cgms, etc either-- ponder that a bit...

In my case my doctor prescribed a few weeks worth and said if I want to continue full time I'd need to do the lung evals--- that is perfectly appropriate.
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