If one considers the lungs a finite space. Much like the inside lining of a balloon (poor analogy for alveolar tree) and considers that SC space is infinite. Much like an ocean. You can see why afrezza will top out at a specific dose hence covering the lining inside the balloon. But this lining is quickly cleaned off (usually within minutes) so additional afrezza can be given shortly afterwards. This causes allot of variability in the insulin kinetics. Also you will note in briefing docs that the reviewer explains this to some degree
The benefits of this is less hypos. But one must be sure to dose enough afrezza and at correct intervals to capture the entire glucose excursion of specific meals. SC insulin is limited in this ability and also logically would have a different PK and PD action than afrezza. Because SC insulin has a longer tail it can be detrimental giving a second dose after eating due to hypos and stacking.
Not really such a great analogy, as you yourself point out, because the alveolar tree has a huge surface area, commonly compared to the size of a tennis court, which is a bit larger than the surface area available for SC injections. This is one reason that drug delivery via the lungs is so promising.
Your right about the large surface area. However unlike the intestines. The absolute surface area of the lung (alveoli) is not used. There are several areas of the lungs that do not exchange gases like O2 located in " dormant" zones. So again yes it is a less than perfect analogy but all anatomical physiogy is unique in itself
My analogy. You have to understand that there is not only a cMax there is also a vMax. Imagine all the receptors in the body for glucose uptake are security checkpoints in the airport. Imagine afrezza is the passengers in the airport. Due to afrezza's rapid cMax peak it quickly overloads the system and achieves the vMax for the system. Adding more afrezza will not increase the velocity of the system. The line only gets longer.
If I may, the "passengers" in your analogy are very efficient passengers though. Although there are fewer lines they move through faster. The RAA (more so regular) insulins keep building longer lines and more of them
Of course the tissue glucose receptors act similarly to monomeric insulin no matter which insulin is circulating. So once it enters blood stream the laws of equalizing will make all insulins work similarly as a general statement. The critical factors are the differences in the kinetics BEFORE it enters the blood stream ( ie SC, alveoli, muscle, spinal cord, intraarticular, etc..)
Kinetic reactions are nonlinear. Everyone here having a very difficult time understanding nonlinear because they are use to dose and effect in a linear fashion. Having basic knowledge in chemical reaction, end point, rate, kinetic would be helpful for those who lack knowledge. If you understand nonlinearity you will understand it is not a problem. I have a hunch the FDA committee members maybe lacking in that area.
We were solo close weren't we?! Now another 2-3 months when all would have been known just 3 days from now. Oh well it matters little by this point. The revolutionary aspects of afrezza will shift all of the prandial market here and globally. But the REAL shift will come later and be much bigger. IMO
That's a great analogy. If correct, and I have no learned reason not to believe it is, it makes it so much easier to visualize it's functionality. It reminds me of a visual presentation made at the recent City of Hope annual conference by a doctor from a Santa Barbara hospital familiar with AFREZZA. He showed how the lungs fill evenly by coating the walls and then the clear just as evenly. Nice. My concern is that the FDA is not equipped to understand this and it was not reinforced enough by the company.
It is not a perfect analogy but then again what is in the human body? I also like the analogy of giving a minivan driver a new Mercedes ZLX class turbo and asking them to drive that around all day while their neighbors keep driving their minivans. This analogy is the flaw of an unblinded and in appropriately controlled comparator trial like 171 was. 175 is a different story all together....