murdainc

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This is a serious question... I understand that giving 2x100mg normal release is equivalent...but does anything change with extended release properties?
 
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Quiksilver

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Well the question being asked truely depends on the absorption kinetics of the drug molecule and the release of the drug from the drug production. XR products like to obtain a zero order absorption rate, which means it is independent of the concentration of the drug.

Assuming a one compartment model:

Cp = F* ko/Vd*ke * (1-e^-ket)
Plasma Concentration = Cp
Bioavailability = F
ko = zero order absorption rate
ke = first order elimination rate
Vd = volume of distribution
t = time

meaning if any of these parameters change as a result of using a 2 x 100 tablet, then your kinetics and plasma concentrations would change and they wouldn't be equivalent. i don't think any would change, unless someone else feels differently.
 
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nnguyenc

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Well the question being asked truely depends on the absorption kinetics of the drug molecule and the release of the drug from the drug production. XR products like to obtain a zero order absorption rate, which means it is independent of the concentration of the drug.

Assuming a one compartment model:

Cp = F* ko/Vd*ke * (1-e^-ket)
Plasma Concentration = Cp
Bioavailability = F
ko = zero order absorption rate
ke = first order elimination rate
Vd = volume of distribution
t = time

meaning if any of these parameters change as a result of using a 2 x 100 tablet, then your kinetics and plasma concentrations would change and they wouldn't be equivalent. i don't think any would change, unless someone else feels differently.

i beat up nerds like this in pharmacy school
 

FruitFly

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play nice folks.. :laugh:
 

murdainc

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Okay, I guess what I'm asking here is... wouldn't the time to release all the medication be shortened with 2x100mg?? Since technically you have two tabs releasing the drug at the same time instead of 1
 

BravoKilo

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Okay, I guess what I'm asking here is... wouldn't the time to release all the medication be shortened with 2x100mg?? Since technically you have two tabs releasing the drug at the same time instead of 1
Theoretically, you're correct... your dissolution rates will most likely be quicker w/ the 2x100 than the 1x200 (though this is dependent on the size of each dosage form). We just discussed a similar question this past semester in pharmaceutics -- don't have my notes with me, but the basic premise is for X mg of drug, the smaller the drug molecule (total volume), the greater the dissolution rate. Basically, in a given amount of space assuming a spherical drug molecule, volume is reduced at a cubic rate of radius, whereas surface area is reduced at a square rate (i.e. V = 4/3*pi*r^3, SA = 4*pi*r^2), so decreasing particle size/radius has a greater effect on volume than it does on surface area. By decreasing overall volume, you increase the total number of particles in a given area/compartment. And by increasing the total number of particles in an area, you also increase the the sum surface areas (which determines dissolution).

The real question instead is whether or not this is significant pharmacologically.
 
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WVUPharm2007

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Yeah...for all practical intents and purposes, it doesn't matter. I substitute two of a lower dosage form to make a larger one all the time.
 

Quiksilver

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i beat up nerds like this in pharmacy school
i cant help it that we were taught kinetics better then you were. but thats okay..... we need someone to count by fives:eek:

Bravo,
with regards to the issue with the dissolution rates being different, yes thats true but the drug release is controlled by drug design. when you are comparing standard release X to standard release Y your idea makes sense and it is perfectly logical.

the difference here is that the drug product does not dissolve completely right away. There are excipients, different salts of drugs and plastic shells that are employed to delay dissolution therefore absorption.

Like i said before, in a controlled release product, absorption is independent of concentration since it is zero order. That means that if there is less drug to work with, it doesn't matter, its released at the same rate irrespective of the amount of drug in there.

If the logic was true that:
1x 200 mg XR does not equal 2x 100 mg XR and the
one product would dissolve faster then the other

then you in an essence would be saying that Ambien CR 6.5 mg will dissolve much faster then Ambien CR 12.5 mg. That in a ambien CR 6.5 mg will not last you the whole night like the 12.5 mg will. I think you can understand that this is not true. The dosing of different strength controlled release products does not change, this is because they are designed to dissolve and release drug at the same rate.
 
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BravoKilo

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I agree that my example didn't exactly pertain to the OP's question, but was rather an example we touched on in class that had similarities.

Your Ambien CR example does bring up a good question however -- and sorry if this is a bit trivial but please bear with me (I'm a P1 so cut me some slack :)), are the dissolution rates between various strengths equal (i.e. identical matricies)? Does a 6.25mg tab in fact take as long as a 12.5mg tab to dissolve? This would imply constructing a new matrix for each strength, with the lower strength tabs having a lower dissolution rate. Or rather, are the half-lives longer than the time it takes to dissolve a given amount of drug, making everything a moot point?
 

Quiksilver

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I agree that my example didn't exactly pertain to the OP's question, but was rather an example we touched on in class that had similarities.

Your Ambien CR example does bring up a good question however -- and sorry if this is a bit trivial but please bear with me (I'm a P1 so cut me some slack :)), are the dissolution rates between various strengths equal (i.e. identical matricies)? Does a 6.25mg tab in fact take as long as a 12.5mg tab to dissolve? This would imply constructing a new matrix for each strength, with the lower strength tabs having a lower dissolution rate. Or rather, are the half-lives longer than the time it takes to dissolve a given amount of drug, making everything a moot point?

You will learn in kinetics that half life is usually only dependent on an elimination constant called k. K is typically dependant on 2 qualities. It may blow your mind now but half life is independent of concentration as well. It will take 4-5 half lives before the drug is at the target concentration and it will take 4-5 half lives before a drug is out of your system completely. drug dose that you take po will decide plasma concentration and NOT half life.

so to answer your question, i am not sure really. I would assume that the matrix is the same for both its not logical for drug companies to put that much research into that. I will have to find you a better answer. i will get back to you
 
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BravoKilo

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I would assume that the matrix is the same for both its not logical for drug companies to put that much research into that. I will have to find you a better answer. i will get back to you
Which is what I was thinking... given identical matrix composition, and relatively similar sizes, their dissolution rates (dm/dt) would/should be equal. In this case, the 6.25mg tab would in fact dissolve sooner than the 12.5 mg tab, assuming its dissolution rate is constant throughout time (which I'm guessing isn't quite the case for either in reality). This would also imply, that while their dissolution rates are equal, 2x 6.25 mg tabs would yield a greater total drug dissolved per unit time than the 1x 12.5 mg tab, but again, they would both fully dissolve twice as quickly.
 

Quiksilver

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Which is what I was thinking... given identical matrix composition, and relatively similar sizes, their dissolution rates (dm/dt) would/should be equal. In this case, the 6.25mg tab would in fact dissolve sooner than the 12.5 mg tab, assuming its dissolution rate is constant throughout time (which I'm guessing isn't quite the case for either in reality). This would also imply, that while their dissolution rates are equal, 2x 6.25 mg tabs would yield a greater total drug dissolved per unit time than the 1x 12.5 mg tab, but again, they would both fully dissolve twice as quickly.
the rate at which the tablet dissolves will be similar but at a given time, there is more drug released with the drug at a higher dose, this is because it has to reach a higher plasma concentration. if 1 12 mg tablet does not release more then a 6.25 mg tablet, we are in trouble. The rules that govern standard release products do not apply to controlled release products.
I think this is easier to conceptualize:
Lets now think that in order to consider this concept that our drug is something like Concerta, this is a controlled release product, it does it by having the drug encased in a plastic shell (that does not dissolve) with a pin hole in it. the excipients then coat the plastic shell. We can control the release of drug by making the pinhole bigger. So for a higher strength drug, the pinhole is bigger. Thus the drug will be delivered within the same amount of time, but the release rate of the drug from product is different.
 

npage148

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what if the release profile or F of the 100's is different than the 200's. Isn't that the case with Niaspan 500's and 750's?

Niaspan PI said:
Absorption

Niacin is rapidly and extensively absorbed (at least 60 to 76% of dose) when administered orally. To maximize bioavailability and reduce the risk of gastrointestinal (GI) upset, administration of NIASPAN® with a low-fat meal or snack is recommended.

Single-dose bioavailability studies have demonstrated that the 500mg and 1000mg tablet strengths are dosage form equivalent but the 500mg and 750mg tablet strengths are not dosage form equivalent.
Distribution
 

PharmDstudent

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what if the release profile or F of the 100's is different than the 200's. Isn't that the case with Niaspan 500's and 750's?
I think that's a bunch of garbage or propaganda by the manufacturer.

blah, blah, blah - "Once titrated, it is important for the patients to take therapeutic doses of Niaspan® as directed in the labeling to avoid the risk of significant flushing early in the initial therapy and hepatotoxicity later in the therapy. That is, patients should take two, 500 mg Niaspan® tablets for a 1000 mg dose, two, 750 mg Niaspan® tablets for a 1500 mg dose and two, 1000 mg Niaspan® tablets for a 2000 mg dose. It is believed that early flushing and subsequent hepatotoxicity can be avoided by following such directions in view of the fact that the 375 mg and 500 mg Niaspan® tablets are not bioequivalent to the 750 mg and 1000 mg Niaspan® tablets, i.e., the 375 mg, 500 mg and 750 mg Niaspan® tablets release niacin at a slower rate than the Niaspan® 1000 mg tablets. Moreover, the 375 mg and 500 mg Niaspan® tablets are believed to release niacin at the slowest rate. Thus, and in accordance with the present invention, early in niacin therapy, when a patient is most susceptible to flush and taking low doses, the patient should receive the slower dissolving Niaspan® tablets to avoid quick saturation of Pathway 2 and to permit the body to desensitize itself from the prostaglandin effects (PDG 2 ) resulting from elevated niacin concentrations, so that flush can be avoided. However, as the patient is titrated to higher doses ( no more than about 500 mg increments at four-week intervals), the Niaspan® tablets used should release their niacin at faster rates to reduce the risk of hepatotoxicity. It is believed that, at this point, the patients prostaglandin system has acclimated itself to niacin and the risk of flush is minimized."- blah, blah, blah. (I didn't know that a belief and a fact were the same thing. :rolleyes:)

As I see it in View attachment Table 4.txt , which shows the percentage released, the % of drug released is very similar for all milligrams of the drug,

and with View attachment Table 9.txt , the range for 1500mg of niacin (3 of the 500mg tablets) can very from an AUC of 6 to 15.7, while 2 of the 750mg tablets resulted in an AUC of 11.5 (which is between 6 and 15.7).

http://www.freepatentsonline.com/6406715.html (patent info, including tables provided in post)

Thanks for bringing up the Niaspan topic npage148. I spent a couple of hours doing research and the like, so perhaps you can consider it a New Years present.


I wish everyone a Happy New Year's!
I'm about to take a walk to City Park with my boytoy. This area of the city is having its annual New Year's Eve bonfire tonight, and I want check it out before we go.
We'll be bringing bottles of bubbly with us later. New Year's is one of my favorite holidays...
 

Quiksilver

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what if the release profile or F of the 100's is different than the 200's. Isn't that the case with Niaspan 500's and 750's?
good find, and equally good find by PharmDstudent.

On an aside, I would think that an important fact is to consider the therapeutic range of the drug, messing with niaspan in not the same as messing with digoxin. Is it therapeutically significant? With the niaspan, we see more flushing with using 750 mg vs 500 mg. We can conquer this with using ASA anyways. So what are the implications, thats the more important question of using a different dosage scheme.
 

npage148

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Interesting stuff about niaspan. Looking at table 9, they appear at first glance that they may not be BE. Look at the Cmax. They are all over the place for the different sized tablets but they same does. To be BE, they need the 90% CI within 20% of each other. So they look like maybe, but without the SD and n, we have no idea. It may also be a problem that niacin is a highly variable drug and showing BE would be a headache. Clinically, I wouldn't imagine much of a problem switching, but scientifically they very well could not be BE
 

Aznfarmerboi

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You will learn in kinetics that half life is usually only dependent on an elimination constant called k. K is typically dependant on 2 qualities. It may blow your mind now but half life is independent of concentration as well. It will take 4-5 half lives before the drug is at the target concentration and it will take 4-5 half lives before a drug is out of your system completely. drug dose that you take po will decide plasma concentration and NOT half life.

so to answer your question, i am not sure really. I would assume that the matrix is the same for both its not logical for drug companies to put that much research into that. I will have to find you a better answer. i will get back to you
While K is independent of concentration (First order I think), and depending on elimination, don't forget that drugs might have different order reactions. Zero order, first order, and mix when at higher doses...

In talking about half life and plasma concentration, let me simplify things for the other posters who might not understand you. Half life is almost strictly relating to elimination. You want to know how long it takes for a drug to be eliminated from the blood system. Hence you do not count half life in deciding plasma concentration because plasma concentration will be drugs you absorbed.
 

PharmDstudent

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good find, and equally good find by PharmDstudent.

On an aside, I would think that an important fact is to consider the therapeutic range of the drug, messing with niaspan in not the same as messing with digoxin. Is it therapeutically significant? With the niaspan, we see more flushing with using 750 mg vs 500 mg. We can conquer this with using ASA anyways. So what are the implications, thats the more important question of using a different dosage scheme.
Thanks!

You're right about the seriousness of niacin vs something like digoxin, but just wait until they start a new field of Pharmacokinetics called: "Niacin Pharmacokinetics". j/k

Interesting stuff about niaspan. Looking at table 9, they appear at first glance that they may not be BE. Look at the Cmax. They are all over the place for the different sized tablets but they same does. To be BE, they need the 90% CI within 20% of each other. So they look like maybe, but without the SD and n, we have no idea. It may also be a problem that niacin is a highly variable drug and showing BE would be a headache. Clinically, I wouldn't imagine much of a problem switching, but scientifically they very well could not be BE
I think you're right. Establishing BE is probably a pain in the *** for niacin, lol, and because of that, the company gets to do all of that fancy schmancy marketing that requires people to buy a totally different prescription instead of just using what they might already have at home left over from their last prescription.

Oh well.

What's strange to me is that the company can say, by default, that their doses are not BE, but they don't really prove that, without a doubt, they are or are not BE. They sit on the word "belief" too much. If the amounts in those tables were more straight forward, then their claim of not being BE would be more legitimate, in my opinion.

What's even worse is that they use the same process to make all of their tablets, there is no real difference between excipients or release time, but yet, they can market some of their doses as not BE. It's strange.

Half life is almost strictly relating to elimination. You want to know how long it takes for a drug to be eliminated from the blood system. Hence you do not count half life in deciding plasma concentration because plasma concentration will be drugs you absorbed.
Also,
Drugs enter the plasma/blood stream before they enter the tissues (an exception, the one compartment model, pertains to drugs that rapidly and evenly distribute between the plasma and the tissues), and it is in the tissues where drugs have their effect, so the absorption that occurs within the plasma does not tell you very much about the drug's effect, unless it is a one compartment model drug.

As the drug is eliminated, the concentration of the drug in the plasma will decrease, but this is measured by the amount of plasma fluid that is filtered, because it is very difficult to say exactly which reactions are contributing to the drug's elimination and where to go within the body to measure elimination. "Drug clearance (body clearance, total body clearance, or Cl T) considers the entire body as a single drug-eliminating system from which many unidentified elimination processes may occur."- from the book: Applied Biopharmaceutics and Pharmacokinetics
In essence, the plasma fluid that is filtered of the drug will be indicative of the drug's half-life, in terms of elimination.

Bravokilo- I didn't take Teaching 101, so hopefully you get all of this. ???
 
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Quiksilver

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While K is independent of concentration (First order I think), and depending on elimination, don't forget that drugs might have different order reactions. Zero order, first order, and mix when at higher doses...

In talking about half life and plasma concentration, let me simplify things for the other posters who might not understand you. Half life is almost strictly relating to elimination. You want to know how long it takes for a drug to be eliminated from the blood system. Hence you do not count half life in deciding plasma concentration because plasma concentration will be drugs you absorbed.
Elimination constant K is zero order when it is independent of concentration. You are correct when saying the elimination rates may change with a high concentration, due largely to the fact that a system may be saturated.But elimination does not play an effect on absorption and would not be critical to the question at hand.

You do bring up a good point, though. The reason elimination rates change is because of saturation of a michelis-menton-like reason. Enzymes get saturated, and therefore rates and rate constants change when enzymes that are working as fast as they can and there is accumulation of drug in a body "compartment".

a tablet can be absorbed by enzyme transport systems and by definition, could be saturated. Their absorption rate would switch to a zero order. However, I am not aware of any drugs that are designed to act in that fashion. If someone knows any, I am interested in knowing. It would only be zero order until the transport catches up with the pooling drug. Interestingly enough this situation would work very similar to a controlled release drug, the absorption rate is zero
 
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