Gabapentin, the wonder drug of psychiatry and its highly debatable AUC

[ThePharmacist4925]

I would like to start out by saying I am not a doctor, never will be a medical doctor, do not really want to be a medical doctor, am not a substitute for a medical doctor or whatever the fuck else people might claim I'm trying to be. I'm just an avid reader that dose research by reading studies, forums, patents, erowid, and doing self-experimentation. I think this shit is fun, don't penalize me for my lack of a college education. Thank you for your consideration and cooperation.

Gabapentin is regularly used, whether as a placebo or not, to treat seizures, anxiety, and nerve/neuropathic pain. I'd say many patients find gabapentin useful and would continue its use even if for some reason they had to pay out of pocket for the prescription. This says something in a world of pharmaceuticals that don't really do much of anything perceived as helpful or curative/palliative by patients. Gabapentin is not magical, but it happens to be more useful than many other drugs.

I've heard of people taking massive quantities in an effort to get high and failing miserably, sure its nice, but given what we know about its pharmacokinetics, taking a massive dosage all at once is naive and relatively pointless in the scheme of drug use. I've also seen people post around the web about their addictions to gabapentin, these reports I find rather odd as people are still taking about 3grams at a time
hoping get high, squandering massive prescriptions in a matter of days. I am an addict, the addiction part I get, but the large doses are just a waste of a good pharmaceutical, you would think people might learn. This is a moot point and I will now move on.

I had the good fortune of meeting with the psychopharmacology expert for both The Menninger Clinic and Mclean Hospital this year. I will state bluntly that Mcleans psychopharmacology expert is clearly an avid textbook connoisseur and I congratulate him on his ability to read and regurgitate medical books; boring guy, relatively unhelpful, didn't tell me anything I wasn't already aware of. The psychopharmacology expert for The Menniger Clinic was very personable and I enjoyed my debate with him over the efficacy of different dosing regiments of gabapentin. I know that the human body can only utilize so much gabapentin at one time. Besides using snacks and Aleve to potentiate it, the body seems to put to use about 200mg of a 300mg capsule give or take every 45 minutes to 90 minutes. More can be squeezed through by increasing bioavailability or taking mass doses, this is generally a waste of gabapentin though. Ultimately the stance of the Menninger psychopharm expert was that the area under the curve was the same dosed at 600mg 3x daily or 300mg 6x daily. I couldn't resolve the area under the curve issue with him, I am sure the AUC for gabapentin must be higher if dosed more often if the daily total dosage is the same. My psychopharmacologist when i was at Austen Riggs declined to comment on the matter, so be it. My outpatient psychiatrist let me switch my dosing from 3x daily to 6x daily with the total still being 1800mgs a day, I felt a difference, placebo maybe, but I sincerely doubt it.

Is there any way a pharmaceutical company could do a new study regarding the bioavailability of gabapentin so I could better understand this weird wonder drug, it perplexes me that so many people take it, but no one is debating about the bioavailability differences between different dosing regimens. I'm aware there wouldn't be money to be made in doing this study, but I want to know what the deal is. Am I right or is the psychopharmacology expert correct, everything I've read leads me to conclude there is much we don't know and I'm more correct regarding the AUC issue.

Pardon the length of this.

 

[sekio]

I mean, on paper, there's no reason you couldn't do your own AUC studies. The problem comes when you need to organize and get consent and corrall more than 2 people together, draw blood, do a quantitation set up to calculate levels of gabapentin, etc.

You really have to know what you're doing, and, to be sure, the experiment has almost certainly been done already by the guys who first develped modafinil. (The FDA requires that kind of data for a new drug application.) It tends to stay trade secrets for whatever reason.

 

[Cotcha Yankinov]

Hi there, about the people taking massive doses vs. taking low doses regularly.. Not to regurgitate Wikipedia, but "gabapentin binds to the α2δ subunit (1 and 2) and has been found to reduce calcium currents after chronic but not acute application" ---http://www.pnas.org/content/105/9/3628.full.pdf

Also, some of the longer term effects may be from the effect on synaptogenesis http://www.cell.com/abstract/S0092-8674(09)01185-4

This would lead me to believe that spreading out the dosage is best. You wouldn't want a gap in doses especially assuming there is up regulation at the alpha 2 delta site right? I could be retarded... I don't know much about that receptor alpha 2 delta type thing..

 

[Kittycat5]

Gabapentin absorption exhibits a saturation process of a transporter so increasing the dose tends to decrease bioavailability. It is very possible that 300mg six times a day will give higher bioavailability than 600mg tid as a result. I believe the BA decreases from 60% to around 35% when given tid at doses of 400 and 1600mg respectively, so you may be on to something.

 

[atara]

A number of acquaintances have reported recreational and even hallucinogenic effects from large doses of gabapentin. I'm not sure where you got the idea that this isn't possible?

In any case the half-life is 6-8 hours but the absorption may be "saturated" according to:

http://mobile.journals.lww.com/clin....aspx?year=1995&issue=12000&article=00001#ath

I suppose that once you achieve a certain tolerance your body won't absorb the stuff rapidly enough to produce the desired effect level. There are ways around this, none of them recommendable, but probably not too hard to figure out. Transporter saturation is likely responsible for the ceiling effect you describe.

 

[aced126]

I had a think about your question about AUC. I used a simple single exponential model to find out the AUC after N dosages at time period T. It was modeled on the fact that rate of change of the concentration of the drug is directly proportional to the drug concentration itself at that time (first order kinetics). The assumptions were as follows.

-iv administration for all doses (I think something similar will come out for oral doses, since the AUC from 0 to infinity for iv and oral both are proportional (with same proportionality constant) to how strong your liver is mainly, although the maths would become severely complicated)
-equal time interval for all doses
-equimolar doses administered each dose.

Using the statistics you gave,
Case 1, dosage=600mg, liver constant (calculated from gabapentin half life of 6 hours) =0.1155, number of dosages=3, time period=2 hours
AUC =13,500 mghours

Case 2, dosage=300mg, same liver constant, number of dosages=6, time period=1 hour
AUC=5000mghours

You're definitely correct that the AUCs will not be the same at all, as shown by this IV calculation. What this suggests is staggered larger doses will result in greater AUC (atleast via IV, haven't considered oral administration at all which might be completely different especially as kittycat said bioavailability isn't even constant).

 

[Kittycat5]

Gabapentin follows zero order kinetics for absorption and is not metabolized by the liver. Can you define liver constant as I think renal excretion would have a greater effect on clearance.

 

[aced126]

Crap all that work, well I kinda made a formula for first order molecules which are mainly excreted due to liver, I don't know how to write maths with latex though, I could post a pic if people are interested...

 

[aced126]

Why does it follow 0 order for absorption? I swear the dosage isn't that high for it to be 0 order? Maybe because the molar mass is low...
I assumed instant absorption anyway (IV admin).

 

[Kittycat5]

Because of the saturation of the transporter plasma levels arent linear to dose.

For IV it maybe first order. Not sure though.

 

[aced126]

Surely for IV there is no absorption?

 

[Kittycat5]

Of course. And I checked about elimination which does follow first order kinetics. Kind of moot as it isnt available IV.

 

[aced126]

I know, my main point was to show that the AUCs would definitely not be the same. My formula holds for first order elimination kinetics, I just thought the main eliminating factor would be liver enzymes. Seems like it doesn't, but I modelled for first order elimination anyway so I guess all that changes is the name of the elimination constant.

Here's the formula I used for anyone interested:

I by mistake wrote k as k2 in the formula, I was thinking about something else; all the ks should be ks.