PTM1 seems hung up on the dosing being the same fr
Post# of 148334
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Posted On: 05/26/2021 7:54:41 AM
PTM1 seems hung up on the dosing being the same from a small woman to a large man. It's not something to worry about. And to your comment about steady state and half life I think you're barking up the right tree.
Any company wishing to bring a drug to market will perform plenty of studies early on to figure out optimal dosing, but that doesn't mean they stop learning and adjusting. From animal studies to human pharmacodynamic and pharmacokinetic studies, they learn as much as they can before choosing a dose and dosing regimen.
Of course we're seeing now with Covid that what worked for HIV may not be quite what we need to work in Covid patients. With what was known about HIV and a little bit of cancer dosing, the first attempts at figuring out Covid dosing were in the public eye of our Phase 2 and 3 trials, rather than through a few years of lab, animal, and human Phase 1 trials. There wasn't time to go the normal route and guesses had to be made. It wasn't far off though, and we're seeing real time adjustments to dosing as we learn more about what exactly is going on with these patients.
The body is generally fairly predictable. If there are receptors in the body and you block them, you interrupt the process those receptors are aiding. Or conversely you can force the activation of those receptors to make something happen that wasn't happening naturally. I think CD12 showed this effect clearly in what was happening at 14 days when LL was present versus 28 days when it was long gone.
There are some things, like insulin (or coumadin), that are dependent on a lot of things happening in and to any one person. Food intake, exercise levels, and each individual's insulin issues (makes none vs body doesn't process it properly, etc) come into play and makes dosing more individualized. Though even then there are still a lot of commonalities surrounding dosing. For instance, Basal vs Bolus needs (low level all day vs meal time spike) is common across all patients.
Then there are other things, like antibiotics, which are often dosed at a consistent level across many ages, weights, or gender. That's because despite the differences in people, our bodies are acting roughly the same against pathogens. Usually. Some of you are freaks. There's no way around that. It's science and statistics.
Most of the drug dose decisions are based around maximizing efficacy while minimizing side effects. When you don't really have side effects (like is the case for LL) you can figure out what the minimal dose is that provides broad efficacy and use that until you find a need to change course for some reason or another.
(By the way, I'm all for dosing at 700mg each week and using IV at the beginning or even consistently throughout treatment for hospitalized patients. Let's blanket the system with LL and ensure we aren't coming up a little short on occasion. It quite literally can not hurt to try based on LL's safety profile)
Where things like IV or a larger first dose come into play is in getting your drug to where it needs to go faster and with greater numbers. Kick start the process, if you will. If you're starving you could walk to a store and buy food, which would solve the problem. But if you hopped in your car and drove you could solve it sooner. IV or larger doses of LL is meant to rush the first contact and then from there a steady state can be reached where the same amount of LL is leaving the body as there is entering the body. At this point receptors are basically always covered by either lingering LL or fresh new LL coming in all dapper and sliding in for those sloppy seconds (or thirds or fourths).
At some point there becomes more LL floating around looking for a receptor to hump (medical term) than there are receptors with their pants down (also a medical term). Sorry to get all technical on you here at the end but I was a pharmaceutical rep for almost a decade and it's easy to slip back into my deep mental catalog of knowledge.
If you want a real concern about dosing it shouldn't be about whether it needs to be different for someone who weighs less than someone else. It should be that it appears that when patients are dischargeable they go home and dosing stops. I'd prefer to see every patient in every trial complete all four doses regardless of if they are getting healthy enough to be discharged. Leave nothing to chance. We saw what happened (or appears to have happened) with mortality after 14 days and then later at 28. Perhaps I'm wrong that they stop dosing if the patient is deemed recovered enough to leave, but it seems like a small thing to ask (that they come back and receive the last one or two doses) to ensure we leave nothing to chance.
Full Disclosure: I only scanned the details of the two trials and must admit the "no bonin' while on mechanical ventilation" part took a lot of my focus. So please accept my apologies if all patients are indeed dosed through the full course of 28 days.
Any company wishing to bring a drug to market will perform plenty of studies early on to figure out optimal dosing, but that doesn't mean they stop learning and adjusting. From animal studies to human pharmacodynamic and pharmacokinetic studies, they learn as much as they can before choosing a dose and dosing regimen.
Of course we're seeing now with Covid that what worked for HIV may not be quite what we need to work in Covid patients. With what was known about HIV and a little bit of cancer dosing, the first attempts at figuring out Covid dosing were in the public eye of our Phase 2 and 3 trials, rather than through a few years of lab, animal, and human Phase 1 trials. There wasn't time to go the normal route and guesses had to be made. It wasn't far off though, and we're seeing real time adjustments to dosing as we learn more about what exactly is going on with these patients.
The body is generally fairly predictable. If there are receptors in the body and you block them, you interrupt the process those receptors are aiding. Or conversely you can force the activation of those receptors to make something happen that wasn't happening naturally. I think CD12 showed this effect clearly in what was happening at 14 days when LL was present versus 28 days when it was long gone.
There are some things, like insulin (or coumadin), that are dependent on a lot of things happening in and to any one person. Food intake, exercise levels, and each individual's insulin issues (makes none vs body doesn't process it properly, etc) come into play and makes dosing more individualized. Though even then there are still a lot of commonalities surrounding dosing. For instance, Basal vs Bolus needs (low level all day vs meal time spike) is common across all patients.
Then there are other things, like antibiotics, which are often dosed at a consistent level across many ages, weights, or gender. That's because despite the differences in people, our bodies are acting roughly the same against pathogens. Usually. Some of you are freaks. There's no way around that. It's science and statistics.
Most of the drug dose decisions are based around maximizing efficacy while minimizing side effects. When you don't really have side effects (like is the case for LL) you can figure out what the minimal dose is that provides broad efficacy and use that until you find a need to change course for some reason or another.
(By the way, I'm all for dosing at 700mg each week and using IV at the beginning or even consistently throughout treatment for hospitalized patients. Let's blanket the system with LL and ensure we aren't coming up a little short on occasion. It quite literally can not hurt to try based on LL's safety profile)
Where things like IV or a larger first dose come into play is in getting your drug to where it needs to go faster and with greater numbers. Kick start the process, if you will. If you're starving you could walk to a store and buy food, which would solve the problem. But if you hopped in your car and drove you could solve it sooner. IV or larger doses of LL is meant to rush the first contact and then from there a steady state can be reached where the same amount of LL is leaving the body as there is entering the body. At this point receptors are basically always covered by either lingering LL or fresh new LL coming in all dapper and sliding in for those sloppy seconds (or thirds or fourths).
At some point there becomes more LL floating around looking for a receptor to hump (medical term) than there are receptors with their pants down (also a medical term). Sorry to get all technical on you here at the end but I was a pharmaceutical rep for almost a decade and it's easy to slip back into my deep mental catalog of knowledge.
If you want a real concern about dosing it shouldn't be about whether it needs to be different for someone who weighs less than someone else. It should be that it appears that when patients are dischargeable they go home and dosing stops. I'd prefer to see every patient in every trial complete all four doses regardless of if they are getting healthy enough to be discharged. Leave nothing to chance. We saw what happened (or appears to have happened) with mortality after 14 days and then later at 28. Perhaps I'm wrong that they stop dosing if the patient is deemed recovered enough to leave, but it seems like a small thing to ask (that they come back and receive the last one or two doses) to ensure we leave nothing to chance.
Full Disclosure: I only scanned the details of the two trials and must admit the "no bonin' while on mechanical ventilation" part took a lot of my focus. So please accept my apologies if all patients are indeed dosed through the full course of 28 days.
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