Perhaps someone can explain the exended release mechanism of vyvanse to me

[jeffpuffer]

I've been doing a lot of thinking and I just don't see how its possible for lisdexamfetamine to actually be an extended release medication... at least not the way its described.

Lisdexamfetamine is supposed to be extended release because in order to turn the lisdex into dex, your body has to cleave off the l-lysine group from the molecule. Supposedly, the extended release is intrinsic to the molecule itself... which means you can only metabolize so much lisdex into dex per hour effectively making the drug last longer. However, this can't be the case because what would stop your body from metabolizing all of the drug at once? I've read that the reason your body only metabolizes a certain amount at a time is because this metabolism is enzyme rate-limited ie, the enzyme that turns lisdex into dex can only turn so many lisdex molecules into dex molecules per hour. Again, this would infact make the lisdex molecule extended release, BUT, if this were the case, larger doses of the med would simply mean the drug lasts longer, not that the drug is stronger. For example, lets say you can metabolise 10mg of lisdex into dex per hour. Eating a 50mg capsule would mean that every hour, you would get 10mg of dex in your system, and this would happen for 5 hours. Eating a 70mg capsule would mean getting 10mg of dex every hour for 7 hours. But we know that larger doses of the drug result in a stronger effect of the drug, which means more of the drug is getting into your system. IF lisdex is metabolized by a rate-limited enzyme, this is not possible. Rate-limited means you can metabolize Xmg per Yunit of time. Thus, larger doses just mean the drug lasts longer (as shown above) not that the drug is stronger. If lisdex's metabolism is infact not rate-limited as it seems, there is nothing stopping your body from turning all of the lisdex into dex at once, which would simply result in the entire dose entering your body at the same time. This would lead to a rapid comeup of the med up to the total capsule dose, and then a gradual decline over X hours as your body metabolizes the dex. In no way though does this match the definition of an extended release. Blood levels of the med wouldn't stay constant and you would peak and then crash over the period of X hours.

Can someone answer why lisdex is considered extended release, and specifically how the extended release works? Because as shown above, if the molecule is intrinsically extended release, rate-limitation of metabolism would not allow for different doses, only different lengths of action. If the molecule is not enzymatically rate-limited, then there's nothing stopping all of the lisdex from being turned into dex at one time and one time only. And in that case, all of the dex would enter your system at once because it'd be the same as eating X amount of dexedrine IR tabs.

I'm very confused.

[trishcan]

You seem to have a better grasp on the mechanics than I can provide, although I have read that Vyvanse is not really "extended-release" because the drug is released essentially all at once, but has a longer half-life. Basically, the drug peaks quickly and levels drop gradually over a long period, assuming it is metabolized properly.

[jeffpuffer]

Originally Posted by trishcan

You seem to have a better grasp on the mechanics than I can provide, although I have read that Vyvanse is not really "extended-release" because the drug is released essentially all at once, but has a longer half-life. Basically, the drug peaks quickly and levels drop gradually over a long period, assuming it is metabolized properly.

If the drug peaked quickly and dropped gradually over time (12 hours), then taking 70mg of vyvanse would be the same as taking 70mg of dexedrine. IE, you would get all the drug all at once and the only reason the drug would stay in your system for an extended amount of time is because you can only get rid of so much dextroamphetamine at a time. When you take enough of any medication, its effects will last longer simply because there's more of the medication in your system and you can only rid yourself of so much per hour. For example, if you took 1mg of xanax, in 4 hours you might be completely back to baseline. If you took 10mg of xanax, you would still be feeling it the next day, though the effects wouldn't be as strong as they were when all 10mg was floating around in your system.. I hope that makes sense. Infact, all the studies I've been reading show that 70mg of lisdex is metabolized to ~60mg of dextroamphetamine within 2 hours. That's not extended release at all, it's just loading your body up with so much dextroamphetamine that it can't get rid of all of it until around 12 hours. This means peaks and troughs, which are the entire reason extended release medication was brought to market... to get rid of them. Extended release medications are supposed to give you the same amount of drug over a long period of time. Every hour, if you measured someones blood concentration of the ideal extended release medication, you would find the exact same amount of drug in their system until the drug was supposed to wear off. Ex 100mg of ideal XR med is to replace 2 doses of instant release med 50mg over a 12 hour period. At hour 1, their should be 50mg in the blood, at hour 2, 50mg, at hour 3, 50mg, hour 4, 50mg.. at hour 6.5, the first 50mg are gone and the second 50mg take place to again provide 50mg, hour 7, 50mg, .. hour 12, 50mg. Hour 13, 0mg.

[trishcan]

I can't comment on the difference between medication delivery systems, but would say that your explanation is precisely why Vyvanse isn't considered "extended release" It's just categorized as "long-acting."

[trishcan]

also, check this thread if you haven't already.

http://www.addforums.com/forums/showthread.php?t=51658

[ADHD Ceilidh]

I seem to recall reading that rate of absorption is also at play here, not due to pill packaging but inherint to the mechanism of active gut transport... Thus causing part of the pseudoextended release effect and also why taking citrus with Vyvanse does not effect absorption but only excretion.

Can't think of where I read that but thus far your logic is sound.

[Kiddder]

Uh....KMiller? Your up!!!

[CptNemo]

http://www.freepatentsonline.com/y2009/0137515.html

Tables 66 and 68 show you how much of the Vyvanse was left unmetabolized(turned in dex) over a given time.

#66 is 25mg Vyvanse

#68 is 75mg Vyvanse

Have fun.
BTW,what I found to be telling:
Look at the SD columns on the right.
Those are the averages of all the subjects,for each hour.

Whether it is 25mg or 75mg,most of the lisdexamfetamine is gone,meaning it has already been converted.

If you are interested in some more info,which is easier to interpret,read posts #18,and higher,for more facts. I consider them better than facts,because all my documentation is provided by the original mfg,and Shire. Please feel free to critique my statements.
I am not an expert,and don't want to spread misinformation by misinterpreting something.
http://www.addforums.com/forums/show...t=51658&page=2

TABLE 66
Individual subject L-lysine-d-amphetamine intact conjugate concentrations and pharmacokinetic
parameters following oral administration of a 25 mg dose of L-lysine-d-amphetamine to humans
	Subject	Subject	Subject	Subject	Subject	Subject	Subject	Subject	Subject	Subject
	102	103	105	107	110	112	113	116	117	120	Mean	SD	CV %
Time Hours
0	0	0	0	0	0	0	0	0	0	0	0	0	0
0.5	4.1	5.5	10.0	0.0	3.6	0.0	9.2	9.6	8.9	0.0	5.1	4.2	82.0
1	9.2	11.2	15.2	12.5	9.1	2.7	20.1	10.5	10.8	10.9	11.2	4.5	39.7
1.5	4.0	4.4	6.1	7.5	3.6	6.2	6.6	2.8	4.2	8.4	5.4	1.8	34.1
2	2.1	1.4	2.5	2.9	1.9	4.0	2.3	0	1.7	3.1	2.2	1.1	48.8
3	0	0	0	0	0	0	0	0	0	0	0	0	0
4	0	0	0	0	0	0	0	0	0	0	0	0	0
5	0	0	0	0	0	0	0	0	0	0	0	0	0
6	0	0	0	0	0	0	0	0	0	0	0	0	0
7	0	0	0	0	0	0	0	0	0	0	0	0	0
8	0	0	0	0	0	0	0	0	0	0	0	0	0
10	0	0	0	0	0	0	0	0	0	0	0	0	0
12	0	0	0	0	0	0	0	0	0	0	0	0	0
16	0	0	0	0	0	0	0	0	0	0	0	0	0
24	0	0	0	0	0	0	0	0	0	0	0	0	0
48	0	0	0	0	0	0	0	0	0	0	0	0	0
72	0	0	0	0	0	0	0	0	0	0	0	0	0
Parameter
AUC last	9.18	10.95	16.31	10.68	8.583	5.439	18.51	10.77	12.35	10.41	11.32	3.74	33.1
(ng · h/mL)
AUC inf	10.62	11.64	17.66	12.65	9.759	—	19.56	—	13.3	12.83	13.50	3.40	25.2
(ng · h/mL)
C max (ng/mL)	9.18	11.2	15.2	12.5	9.05	6.18	20.1	10.5	10.8	10.9	11.56	3.80	32.9
T max (hours)	1	1	1	1	1	1.5	1	1	1	1	1.05	0.16	15.1
T 1/2 (hours)	0.47	0.34	0.38	0.47	0.44	—	0.32	—	0.38	0.55	0.419	0.077	18.5

TABLE 67
Individual subject d-amphetamine concentrations and pharmacokinetic parameters following oral
administration of a 75 mg dose of L-lysine-d-amphetamine to humans
	Subject	Subject	Subject	Subject	Subject	Subject	Subject	Subject	Subject	Subject
	101	104	106	108	109	111	114	115	118	119	Mean	SD	CV %
Time Hours
0	0	0	0	0	0	0	0	0	0	0	0	0	0
0.5	0	0.748	0.506	0	0	0.779	0.525	0	3	1.85	0.7	1.0	132.2
1	11.9	14.4	12.6	7.26	5.9	10.3	7.2	23.1	23	27.9	14.4	7.7	53.6
1.5	40.3	34.6	30.4	22.8	19.3	38.4	19	52.8	51.5	55.8	36.5	13.8	37.8
2	84.6	48.9	68.2	34.8	32.7	57.2	33.1	91.3	61.7	70.4	58.3	21.0	36.0
3	72.9	64.3	55.7	60.3	62.3	61.1	44.8	95.8	62.1	83.6	66.3	14.5	21.9
4	84.6	65.3	58.8	51.1	77.9	63.3	47.6	89.2	54.2	86	67.8	15.5	22.8
5	65	55.6	60.2	74	83.9	59.1	56.9	77.7	54.9	82.8	67.0	11.5	17.2
6	71	53.5	49.4	51.5	78.3	50.8	55.1	68.8	52.9	64	59.5	10.2	17.1
7	53.8	55.7	52.9	69.5	73.1	52.9	55.9	71.2	45.1	74.6	60.5	10.5	17.4
8	63.7	40.3	47.3	45.7	72.2	46.5	54.2	61.1	44.3	66.2	54.2	10.9	20.2
10	43.7	41.7	37	58.4	67	44.3	48.4	68	34.1	55.9	49.9	11.9	24.0
12	46.4	26.1	36.7	37.4	49.9	32.4	37.1	54.1	34.5	45.1	40.0	8.6	21.6
16	35.4	22.2	25.7	48	44.9	24.3	28.9	44.7	31.7	34.5	34.0	9.2	27.1
24	16.4	11.4	14.9	13.2	18.4	16.8	20.5	21.7	15.7	18.1	16.7	3.1	18.8
48	2.74	2.14		4.17	2.73	3.75	4.81	2.81	4.26	3.36	3.4	0.9	25.9
72	0	0	0	1.07	0.661	0.687	1.49	0	0	0.553	0.4	0.5	120.2
Parameter
AUC 0-12 h	666.2	525.9	531.6	570.3	704.8	545.6	513.7	790.9	523.4	742.8	611.5	104.5	17.1
(ng · h/mL)
AUC last	1266	918.7	1031	1257	1442	1123	1223	1549	1143	1417	1237.0	194.0	15.7
(ng · h/mL)
AUC inf	1301	948.3	1072	1278	1451	1133	1251	1582	1154	1425	1259.5	191.3	15.2
(ng · h/mL)
C max (ng/mL)	84.6	65.3	68.2	74	83.9	63.3	56.9	95.8	62.1	86	74.0	12.9	17.4
T max (hours)	4	4	2	5	5	4	5	3	3	4	3.9	1.0	25.5
T 1/2 (hours)	8.78	9.59	10.02	13.26	9.24	10.41	12.8	8.05	10.92	9.47	10.3	1.7	16.3

TABLE 68
Individual subject L-lysine-d-amphetamine intact conjugate concentrations and pharmacokinetic
parameters following oral administration of a 75 mg dose of L-lysine-d-amphetamine to humans
	Subject	Subject	Subject	Subject	Subject	Subject	Subject	Subject	Subject	Subject
	101	104	106	108	109	111	114	115	118	119	Mean	SD	CV %
Time Hours
0	0	0	0	0	0	0	0	0	0	0	0	0	0
0.5	10.4	22.6	6.92	10.3	0	9.21	7.88	14.5	87.8	35.5	20.5	25.6	124.7
1	48	40.5	29	41.5	21.2	30.8	23.4	127	88.9	80.1	53.0	34.6	65.2
1.5	28.4	15.7	16.1	20.3	26.5	19	12.7	38.7	28.6	38	24.4	9.2	37.5
2	8.87	5.53	4.91	9	18.1	5.62	6.29	12.1	9.75	11.3	9.1	4.0	44.0
3	2.15	1.29	1.76	1.82	10.6	0	2.31	2.57	1.73	1.73	2.6	2.9	111.6
4	0	0	1.09	0	4.65	0	1.53	1.01	0	0	0.8	1.5	176.9
5	0	0	0	0	0	0	0	0	0	0	0	0	0
6	0	0	0	0	0	0	0	0	0	0	0	0	0
7	0	0	0	0	0	0	0	0	0	0	0	0	0
8	0	0	0	0	0	0	0	0	0	0	0	0	0
10	0	0	0	0	0	0	0	0	0	0	0	0	0
12	0	0	0	0	0	0	0	0	0	0	0	0	0
16	0	0	0	0	0	0	0	0	0	0	0	0	0
24	0	0	0	0	0	0	0	0	0	0	0	0	0
48	0	0	0	0	0	0	0	0	0	0	0	0	0
72	0	0	0	0	0	0	0	0	0	0	0	0	0
Parameter
AUC last	51.2	44.2	32.0	43.7	50.4	30.9	29.8	102.1	110.8	86.1	58.1	30.2	52.0
(ng · h/mL)
AUC inf	52.5	45.0	33.0	44.9	52.3	34.2	31.4	102.9	111.7	87.0	59.5	29.9	50.2
(ng · h/mL)
C max	48.0	40.5	29.0	41.5	26.5	30.8	23.4	127.0	88.9	80.1	53.6	34.1	63.6
(ng/mL)
T max (hours)	1	1	1	1	1.5	1	1	1	1	1	1.05	0.16	15.1
T 1/2 (hours)	0.43	0.4	0.61	0.43	1.02	0.41	0.75	0.56	0.38	0.35	0.534	0.211	39.6

[CptNemo]

Dang.
My edit time expired.
I meant to say:

Whether it is 25mg or 75mg,most of the lisdexamfetamine is gone,meaning it has already been converted,in just over an hour.

[jeffpuffer]

Originally Posted by CptNemo

Whether it is 25mg or 75mg,most of the lisdexamfetamine is gone,meaning it has already been converted,in just over an hour.

Correct, which was the entire point of my thread. There are 1 of 2 scenarios which I thought possible.

1. lisdex's metabolism to dex via hydrolysis is enzymatically rate-limited. IE only so much lisdex can be turned into dex per hour. This would truely make lisdex an extended release drug with its release mechanism being intrinsic to the molecule itself. However, like I said, if this is the case, then higher doses just mean longer duration of action since you would only be able to convert so much lisdex to dex per hour. The more you take, the longer the excess lisdex sits around waiting to gete turned into dex and thus the longer the action of the drug. While this would be very neat, it also defeats the purpose of having more than once dosage of the drug since no matter the dosage, the same amount of drug gets delivered per hour.

2. All the lisdex is converted to dex in the gut within an hour or so, and this conversion is not rate-limited. This would allow for different doses to have stronger or weaker effects, unlike the scenario posed above in #1. BUT, if all the lisdex is converted within an hour or so, there's NOTHING extended release about that. After having spent 5 or 6 hours researching all kinds of journals and studies (I have access to every published journal, including the ones you have to pay for, because of my university), I can easily conclude that this is what happens with vyvanse.

The reason it "lasts 12 hours" is not because it's an extended release medication, it's because vyvanse dumps a ton of dex into your system which then takes 12 hours (more or less, depending on the person) to get rid of. Again, THIS IS NOT EXTENDED RELEASE. You can see from the charts that blood levels of dex slowely decline after an enormous peak approxiately 3 hours after taking the medicine. If you were to take 5mg of dexedrine it would probably last you 3 - 5 hours (for theraputic effects, at least). If you were to take 20mg of dexedrine, you would notice theraputic effects for well over 3-5 hours because your body can only rid itself of so much dex at a time.

If vyvanse is "long acting" or "extended release", then so is taking 3 times your normal dose of adderall IR, or Xanax IR.

[CptNemo]

Sorry, I thought my post answered that.
It was cluttered with stuff though!

I think the evidence points to #1.
But only for mammals the size of whales.
So for humans,I'm going with #2.

If you look at the data I provided,25mg,75mg,and 150mg all show the same bioequivalence,as a function of Cmax/Time,as plain ol' dex.

Furthermore,the main difference is that dex begins to work sooner. I think that's desireable.

Vyvanse is not claimed to be "extended release",as Trishcan pointed out to you on another thread.

They claim it is long lasting. It is,for the most part.
So is dex,and the same levels.

I believe Shire's info,if to be believed,shows that in normal dosage (2x mfg suggested max),it releases it self in the same manner as dex,after the drug is metabolized,which takes just over an hour.

Vyvanse is more difficult to abuse at normal doses,with non-approved administration.

Vyvanse is more difficult to abuse orally,but in doses that no one except doctors and pharmacists should be expected to have access to...like 100x my daily dose,at one time.

This shows that however the prodrug is metabolized,it does have a max absorption rate.

None of the studies sponsored by Shire or New River have actually demonstrated exaclty at what dose this max absorption takes place.

Nor have I been able to find a dissolution graph for it.

When I find documents,usually buried at the FDA site,many have pages missing,and they are listed as trade secrets. Just like snake oil has trade secrets,I suppose.

This is only my opinion,but is that what you're asking?


PS: They did alot of tests with common/household chemicals,to show that the bond is hard to break,without the right 'key'.
I have a favor to ask,Jeff. I will PM you

[provoloney]

I think since Vyvanse is the first stimulant I've ever taken, I don't know what is unique to Vyvanse, and what is just amphetamines in general. Doctors seem to love talking about how much their patients love Vyvanse, but I wonder why the feedback on this board is so mixed, and why I'm having a hell of a time finding the right dose. I think I'm going to be going to ask to switch to twice a day dosing soon (at half the normal dose), but at that point, I wonder if it wouldn't make more sense to just try something else. Speaking of which, it seems like Adderall XR might have a better/more complex time-release mechanism, in which case I don't understand why so many people are switching to Vyvanse.

Also, my understanding is that there used to be an older version of Vyvanse (dexedrine Spansules), that had a peak effect at 8 hours or so. Wouldn't that make it longer lasting than Vyvanse?

[jeffpuffer]

Originally Posted by provoloney

Speaking of which, it seems like Adderall XR might have a better/more complex time-release mechanism, in which case I don't understand why so many people are switching to Vyvanse.

Also, my understanding is that there used to be an older version of Vyvanse (dexedrine Spansules), that had a peak effect at 8 hours or so. Wouldn't that make it longer lasting than Vyvanse?

Dexedrine spansules are more effective as extended release medication. Vyvanse isn't actually extended release (read the whole thread if you want to know why). You can get the same effect quicker and cheaper from instant release dexedrine, as you can vyvanse.

So many people are switching to vyvanse because it's new and they're intrigued by it (you can dress a turd up however you want, but it's still a turd), and because the drug reps at shire have been pimping it to doctors for the past 2.5 years because their patent on adderall XR expired and they stood to lose all their money. Doctors are under the impression that vyvanse is some how new, unique, and different from all the other adhd stims, that it can't be abused, and that it's more effective than any other drug. Doctors are wrong. Doctors don't do their own research. If you want to try a new med, I recommend Dexedrine 10mg instant release tabs.

[provoloney]

Thanks for the response; this thread is exactly what I was looking for. I was trying to figure out if it was just me or....

Actually, a comparison of table 67 and 69 is intriguing (vyvanse vs. adderall xr). Adderall xr looks like it lasts LONGER than vyvanse. Again, I've never actually taken it, so I have business speculating.

Any reason for dex IR over the spansule? What I'm really looking for is a medicine that can truly be taken once a day and doesn't make me irritated as hell for hours 7-16. My doc keeps saying that raising the dose will make it last longer, which is probably true, but then hours 1-6 will be way too intense for me. (I'm currently taking 50 mg Vyvanse -- hours 1-6 are perfect though a bit too much).

Part of me wants to just give up on stimulants, but I realize there are other medications. Does anyone actually dose the dex. spansule once a day? It's peak is so late compared to vyvanse (8 vs. 4 hours), which makes me think it really could be a once-a-day medicine, but I have no idea. My doc (whose a GP and I prefer to stick with her for various reasons) only seems to know vyvanse, adderall, and concerta, but will work with me if want to try something else, but I don't think she'll let me try a bunch of different things until I find one I like, so I'm putting a lot of thought into what my next trial should be. [Money is not a huge factor by the way, since insurance is covering.]

[Vickie]

Originally Posted by provoloney

I think since Vyvanse is the first stimulant I've ever taken, I don't know what is unique to Vyvanse, and what is just amphetamines in general. Doctors seem to love talking about how much their patients love Vyvanse, but I wonder why the feedback on this board is so mixed, and why I'm having a hell of a time finding the right dose.

People who get diagnosed and treated without any issues do not have much of a reason to come to places like this. Those that have problems search for help. I came here when educating myself about my kid's ADHD and treatments to help me be a better partner with the doc in the treatment of my kids. Then I was diagnosed and started treatment. Vyvanse is also my first stimulant and I really like how well it works for me, but will reserve final judgment until after I have been on the same dose for a year (right now only a few months at this dose). It is reassuring that I have other options.