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Post by matt on May 19, 2016 8:57:02 GMT -5
Don't confuse pharmacokinetics (how quickly a drug gets to where it needs to be) with pharmacodynamics (how long the drug takes to have its effects). Afrezza is absorbed very quickly so it has an extremely short PK, but its onset of activity (PD) is not significantly different from injected insulin. In other words, despite being absorbed into the blood stream more quickly than injected insulin, it acts on the cells at about the same rate as injected insulin does.
All drugs have to go through ADME testing (absorption, distribution, metabolism, excretion) and the information I describe above is included in the prescribing information that is approved by the FDA. If you read the Afrezza label in detail (and physicians certainly do) it does not describe a mechanism of action that is any different from injectable insulin, or a reduced risk of hypoglycemia. While the drug still has the advantage of inhalation versus needle pricks, the data is not there to support any other conclusions and ultimately if the data is not reflected on the label copy is cannot be used as a marketing claim by the sales force.
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Post by tchalaa on May 19, 2016 9:23:03 GMT -5
Don't confuse pharmacokinetics (how quickly a drug gets to where it needs to be) with pharmacodynamics (how long the drug takes to have its effects). Afrezza is absorbed very quickly so it has an extremely short PK, but its onset of activity (PD) is not significantly different from injected insulin. In other words, despite being absorbed into the blood stream more quickly than injected insulin, it acts on the cells at about the same rate as injected insulin does. All drugs have to go through ADME testing (absorption, distribution, metabolism, excretion) and the information I describe above is included in the prescribing information that is approved by the FDA. If you read the Afrezza label in detail (and physicians certainly do) it does not describe a mechanism of action that is any different from injectable insulin, or a reduced risk of hypoglycemia. While the drug still has the advantage of inhalation versus needle pricks, the data is not there to support any other conclusions and ultimately if the data is not reflected on the label copy is cannot be used as a marketing claim by the sales force. Insulin Chart Each insulin has its own unique therapeutic effect. The onset of action of a particular insulin is how long it takes the hormone to start working at lowering blood glucose levels. The insulin peak is the point at which the dose is at the height of its therapeutic effectiveness, and the duration is how long the blood glucose lowering effect of a given insulin lasts from injection to end. Following is a list of insulin types available in the United States, along with their onset, peak, and duration. Talk to your healthcare provider about your insulin regimen. Insulin preparation Onset of action Peak Duration of action Lispro (Humalog) <15 minutes 1-2 hours 3-6 hours Aspart (Novolog) <15 minutes 1-2 hours 3-6 hours Glulisine (Apidra) <15 minutes 1-2 hours 3-6 hours Afrezza <15 minutes Approx. 50 minutes 2-3 hoursRegular (Novolin R, Humulin R) 30-60 minutes 2-4 hours 6-10 hours Humulin R Regular U-500 30-60 minutes 2-4 hours Up to 24 hours NPH (Novolin N, Humulin N, ReliOn) 2-4 hours 4-8 hours 10-18 hours Glargine (Lantus) 1-2 hours Usually no peak Up to 24 hours Detemir (Levemir) 1-2 hours Usually no peak ** Up to 24 hours** Glargine Injection (Toujeo) 6 hours No true peak 24-36 hours Premixed Insulins*** Onset of action Peak Duration of action Novolin 70/30, Humulin 70/30 30-60 minutes 2-10 hours 10-18 hours Humalog 75/25, Novolog 70/30, Humalog 50/50 10-30 minutes 1-6 hours 10-14 hours Afrezza, a rapid-acting, inhalable form of insulin is now available as well. For more information on Afrezza, click here. *Information derived from a combination of manufacturer's prescribing information and clinical studies. Individual response to insulin preparations may vary. **Peak and length of action may depend on size of dose and length of time since initiation of therapy ***Premixed insulins are more variable in peak and duration of action. For instance, even though the literature states that the effects may last for up to 24 hours many people find that they will need to take a dose every 10-12 hours. Source: www.dlife.com/diabetes/insulin/about_insulin/insulin-chart |
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Post by peppy on May 19, 2016 10:00:22 GMT -5
Matt down under was the first to say it. Afrezza technosphere insulin has a phase 1. Per Matt, a paraphrase, you do not get a phase 1 with other insulin analogs, hexamers. subq.
That is the beauty of afrezza, it stops glucose levels from going high in the first place. this is true. this is what the tee shirts need to say, and the clamp studies need to differentiate.
"Afrezza, stops glucose levels from going high in the first place." screencast.com/t/nT2lnwExjJ
tchalaa, nice post!
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Post by lakon on May 19, 2016 10:16:52 GMT -5
Matt down under was the first to say it. Afrezza technosphere insulin has a phase 1. Per Matt, a paraphrase, you do not get a phase 1 with other insulin analogs, hexamers. subq.
That is the beauty of afrezza, it stops glucose levels from going high in the first place. this is true. this is what the tee shirts need to say, and the clamp studies need to differentiate.
"Afrezza, stops glucose levels from going high in the first place." screencast.com/t/nT2lnwExjJ
tchalaa, nice post! There was at least one person who beat him by over a decade. Besides Al Mann, MattB was probably the first patient to say it so well.  |
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Post by agedhippie on May 19, 2016 10:23:23 GMT -5
Matt down under was the first to say it. Afrezza technosphere insulin has a phase 1. Per Matt, a paraphrase, you do not get a phase 1 with other insulin analogs, hexamers. subq.
That is the beauty of afrezza, it stops glucose levels from going high in the first place. this is true. this is what the tee shirts need to say, and the clamp studies need to differentiate.
"Afrezza, stops glucose levels from going high in the first place." screencast.com/t/nT2lnwExjJ
tchalaa, nice post!
I think Matt's point is that Afrezza arrives fast (PK) but the glucose lowering impact (PD) is only slightly faster than analogs which is what doctors care about. This is the PD graph provided by Mannkind.  |
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Post by mnholdem on May 19, 2016 10:47:15 GMT -5
The chart above that graphically illustrates Afrezza's Infusion Rate (GIR) is certainly one among many other key measurements to look at. I think what Al Mann was excited about (and later Matt in Australia later emphasized in his blogs) was that the speed of Afrezza is what enables it to imitate the 1st Phase insulin release of a healthy pancreas. RAA insulin is much faster than regular SQ insulin, but nowhere near the speed achieved by Afrezza, which enters the bloodstream as a ready-to-use monomer insulin. All types of insulin, given time, break down into similar components and eventually evacuate. Much education is needed on how critical the 1st Phase insulin release by the pancreas is to other physiological actions that are triggered. Peppy's point about signaling the liver is an example.
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Post by agedhippie on May 19, 2016 10:56:53 GMT -5
That's the PK graph and shows how fast the insulin gets into the blood, not how fast it lowers the glucose levels (PD). Doctors care about the PD and not very much about the PK. This may well be mistaken if the insulin level (PK) signals the liver. The problem is that this is rather advanced for most doctors.
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Post by peppy on May 19, 2016 10:59:50 GMT -5
Matt down under was the first to say it. Afrezza technosphere insulin has a phase 1. Per Matt, a paraphrase, you do not get a phase 1 with other insulin analogs, hexamers. subq.
That is the beauty of afrezza, it stops glucose levels from going high in the first place. this is true. this is what the tee shirts need to say, and the clamp studies need to differentiate.
"Afrezza, stops glucose levels from going high in the first place." screencast.com/t/nT2lnwExjJ
tchalaa, nice post!
I think Matt's point is that Afrezza arrives fast (PK) but the glucose lowering impact (PD) is only slightly faster than analogs which is what doctors care about. This is the PD graph provided by Mannkind. I hear you at every level. Physicians can add. They do have a high level of intelligence. I want to talk something over with you, and I am guaranteed to say it badly. Here it is said badly. Correct my thinking where I am incorrect. Does Afrezza offer in some sense two medications in one, in this regard. The initial large hit of insulin to the liver cells stops the liver from making glucose from glycogen. in that sense, the 1st phase afrezza acts a bit like the GLP 1 inhibitors? Then phase two takes glucose levels down the dimers that formed breaking up?
SO the QUESTION: DOES the 1st phase afrezza acts a bit like the GLP 1 inhibitors? Where am I incorrect in my thinking? If it does am I correct thinking, two, two, two hits in one? like the Wrigley commericals? signed, help me out here....
Glucagon-like peptide-1 receptor agonists also known as GLP-1 receptor agonists or incretin mimetics are agonists of the GLP-1 receptor. This class of drugs is used for the treatment of type 2 diabetes.[1] One of their advantages over older insulin secretagogues, such as sulfonylureas or meglitinides, is that they have a lower risk of causing hypoglycemia.[2]
There is some concern over the safety profile of these drugs due to proliferative effects in the pancreas. At the same time, diabetes is associated with both acute pancreatitis and pancreatic cancer, and the most recent studies have not found that these drugs can cause either pancreatitis or cancer.[3]
Approved GLP-1 agonists:
exenatide (Byetta/Bydureon), approved in 2005/2012
liraglutide (Victoza, Saxenda), approved 2010[4]
lixisenatide (Lyxumia), approved in EU 2013[5]
albiglutide (Tanzeum), approved in 2014 by GSK[6]
dulaglutide (Trulicity), approved in 2014 - manufactured by Eli Lily K[7]
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Post by Deleted on May 19, 2016 11:02:28 GMT -5
That's the PK graph and shows how fast the insulin gets into the blood, not how fast it lowers the glucose levels (PD). Doctors care about the PD and not very much about the PK. This may well be mistaken if the insulin level (PK) signals the liver. The problem is that this is rather advanced for most doctors. incase of insulin , PK matters more cos of first phase / second phase.. The rate of lowering will be the same cos its insulin.. like water flow.. water flows at the same rate , but its the volume pumped by time that matters |
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Post by lakon on May 19, 2016 11:36:34 GMT -5
That's the PK graph and shows how fast the insulin gets into the blood, not how fast it lowers the glucose levels (PD). Doctors care about the PD and not very much about the PK. This may well be mistaken if the insulin level (PK) signals the liver. The problem is that this is rather advanced for most doctors. You made a good point. Those doctors are wrong. Both [PK/PD] matter. The FDA had the same difficulty understanding the importance of the PK because they had the myopic view of insulin lowers blood glucose. What else could we be talking about? How about first stopping glucose release into the blood. Signaling. Then forcing glucose out of the blood and into cells. Dynamics. That's why bodybuilders are getting so much bigger these days. Wait until they get a whiff of Afrezza. It's going to be another leg up on the size of these guys and gals. We are starting to see the beginning of the superman [hulk], at least physically. Get all these hormones on Technosphere, and we can start programming our bodies in real-time... These human hormones are not "drugs", and the FDA needs to go away. They should have no authority on the matter, but they do in the USA. I think that some cellular biologists could be helpful in this pursuit. Also, I think that the Chinese could really wrap their heads around this from the Chinese medicinal approach of balancing the energy flows in the body. They were probably on to something, but did not really have the knowledge to push it down to hormones and cellular signaling. Cracking this nut is BIG. The other aspect is to recognize that the area under the curve between the two on the PD graph is important. It's the difference between life and death. Unfortunately, the FDA had it all backwards, and apparently, so does conventional wisdom that is not so wise as it turns out. It was funny at the ADCOM when the one doctor corrected the idiot from the FDA who spoke up about it, but got his facts wrong. Oh well, the world is still flat for a while longer. |
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Post by peppy on May 19, 2016 12:10:15 GMT -5
That's the PK graph and shows how fast the insulin gets into the blood, not how fast it lowers the glucose levels (PD). Doctors care about the PD and not very much about the PK. This may well be mistaken if the insulin level (PK) signals the liver. The problem is that this is rather advanced for most doctors. You made a good point. Those doctors are wrong. Both [PK/PD] matter. The FDA had the same difficulty understanding the importance of the PK because they had the myopic view of insulin lowers blood glucose. What else could we be talking about? How about first stopping glucose release into the blood. Signaling. Then forcing glucose out of the blood and into cells. Dynamics. That's why bodybuilders are getting so much bigger these days. Wait until they get a whiff of Afrezza. It's going to be another leg up on the size of these guys and gals. We are starting to see the beginning of the superman [hulk], at least physically. Get all these hormones on Technosphere, and we can start programming our bodies in real-time... These human hormones are not "drugs", and the FDA needs to go away. They should have no authority on the matter, but they do in the USA. I think that some cellular biologists could be helpful in this pursuit. Also, I think that the Chinese could really wrap their heads around this from the Chinese medicinal approach of balancing the energy flows in the body. They were probably on to something, but did not really have the knowledge to push it down to hormones and cellular signaling. Cracking this nut is BIG. The other aspect is to recognize that the area under the curve between the two on the PD graph is important. It's the difference between life and death. Unfortunately, the FDA had it all backwards, and apparently, so does conventional wisdom that is not so wise as it turns out. It was funny at the ADCOM when the one doctor corrected the idiot from the FDA who spoke up about it, but got his facts wrong. Oh well, the world is still flat for a while longer. Thanks Lakon Matt charts 
afrezzadownunder.com/2015/09/afrezza-units-insulincarb-ratios/
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Post by mnholdem on May 19, 2016 12:15:05 GMT -5
FDA trial data seemed to show that Afrezza was faster in both PK and PD graphs...at least in this trial:
Do you notice how similar the header is to one of the new publications planned for release at ADA-2016?
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Post by lakon on May 19, 2016 12:53:55 GMT -5
FDA trial data seemed to show that Afrezza was faster in both PK and PD graphs...at least in this trial: ...
Do you notice how similar the header is to one of the new publications planned for release at ADA-2016? I am looking forward to it. I always felt that some of the PD graphs were a bit peculiar. It seemed to me that Al [Mann] was onto something about taking the dose at the correct time, probably about 15 minutes into the meal. The FDA did not seem interested in science as much as making sure that it was a "fair" comparison. That should change eventually since there is no fair comparison between a Ferrari and a Pinto. Personally, I cannot wait until Afrezza is OTC and the RAA's are off the market, but my opinions can tend toward the extreme outlier group.  |
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Post by agedhippie on May 19, 2016 15:44:47 GMT -5
I want to talk something over with you, and I am guaranteed to say it badly. Here it is said badly. Correct my thinking where I am incorrect. Does Afrezza offer in some sense two medications in one, in this regard. The initial large hit of insulin to the liver cells stops the liver from making glucose from glycogen. in that sense, the 1st phase afrezza acts a bit like the GLP 1 inhibitors? Then phase two takes glucose levels down the dimers that formed breaking up?
SO the QUESTION: DOES the 1st phase afrezza acts a bit like the GLP 1 inhibitors? Where am I incorrect in my thinking? If it does am I correct thinking, two, two, two hits in one? like the Wrigley commericals? signed, help me out here....
Glucagon-like peptide-1 receptor agonists also known as GLP-1 receptor agonists or incretin mimetics are agonists of the GLP-1 receptor. This class of drugs is used for the treatment of type 2 diabetes.[1] One of their advantages over older insulin secretagogues, such as sulfonylureas or meglitinides, is that they have a lower risk of causing hypoglycemia.[2]
There is some concern over the safety profile of these drugs due to proliferative effects in the pancreas. At the same time, diabetes is associated with both acute pancreatitis and pancreatic cancer, and the most recent studies have not found that these drugs can cause either pancreatitis or cancer.[3]
Approved GLP-1 agonists:
exenatide (Byetta/Bydureon), approved in 2005/2012
liraglutide (Victoza, Saxenda), approved 2010[4]
lixisenatide (Lyxumia), approved in EU 2013[5]
albiglutide (Tanzeum), approved in 2014 by GSK[6]
dulaglutide (Trulicity), approved in 2014 - manufactured by Eli Lily K[7]
I think that is exactly how it behaves. Part of the problem in Type 1 is that in parallel with the insulin is a glucagon release which is designed to mop up excess insulin. The insulin release obviously never happens, but the glucagon release does. My theory is that the insulin signals to stop this which results in the loss of the spike that that glucagon release would cause. I think this is why the first phase response matters because inherently it's quite weak - the second phase response is the one that cleans up the glucose from the food. I need to go and hit the textbooks again! |
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Post by agedhippie on May 19, 2016 15:49:49 GMT -5
FDA trial data seemed to show that Afrezza was faster in both PK and PD graphs...at least in this trial: ...
Do you notice how similar the header is to one of the new publications planned for release at ADA-2016? I did wonder if that was why they redid the PK/PD study. The graph I had came from the prescribing information which is the one the doctors will look at. The study may be in order to change the graph used in the prescribing information and I expect since they are presenting the results at ADA 2016 they got what they were after and it looks more like the graph you posted. |
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