levetiracetam’s half-life, elimination metabolism, drug-drug & drug-food interactions, how long until levetiracetam clears your system and more

Consumer Reviews & Comments | KeppraPagesIndex | Mechanism/Methods of Action/How it Works
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1.  In a Nutshell

Pharmacokinetics (PK)1 is what your body does to a drug, as well as what a drug does to your body in specific ways that usually don’t have much to do with most of the effects of most crazy meds. Unless you count side effects. Pharmacokinetics is a geek’s paradise. This is hardcore, detailed, technical information about a medication2 that explains things like drug-drug interactions, how long it takes to work, why you get certain side effects, and a lot more. Maybe even why some of the meds work the way they do after all. Explaining the various aspects of PK is so long and involved it requires its own page.

2.  How Long Keppra (levetiracetam) Hangs Around

The numbers here are known as “plasma clearance,” which is how long it takes until there is no significant amount of a drug in your blood. I.e. you’re clear of it. How that is determined is very simple: the half-life times five.3

Half-life is the average time it takes for you to metabolize4 half of the drug’s active ingredient. If a drug has a half-life of around 24 hours and you take a dose of 100mg, you’ll have roughly the equivalent a 50mg dose after one day, a 25mg dose after two days, and so on.

The more-accurate complete clearance requires a hell of a lot more data, often, but not always including your weight and the dosage you’re taking. There may also be numerous passes required to fully metabolize a drug, and that applies even to medications that don’t have active metabolites! If we have the data, which we usually don’t, we’ll provide the best estimate we have for how long it really takes for a drug to clear your system. The data we need are found below in the bioavailability section and miscellaneous PK data because we rarely see them section. The formulae vary slightly depending on drug’s pharmacokinetics and how much we know about it. Dosage divided by AUC is the next step up in complexity. We can ratchet it up to Cp(t) = ((dosage * ka)/(V/F)*((ka - (CL/V)))*(e-(CL/V)*t - e-(CL/ka)*t), or even more complicated formulae. To make matters worse, practically all the data come from a small sample of professional lab rats healthy volunteers.

The stupid thing is: complete clearance usually winds up being 2–5 days after plasma clearance no matter what5, but can take weeks. Sometimes a drug will clear from your brain and other organs before it clears from your blood. Prozac is one such drug, but with a half-life measured in days, that doesn’t surprise me too much.

2.1  Plasma Half-Life

levetiracetam has a plasma half-life of: Keppra XR: 7 hours. Keppra IR: 6–8 hours.

2.2  Estimated Time levetiracetam is Cleared/Eliminated from your System

levetiracetam has an estimated plasma clearance of: About two days.

3.  How levetiracetam is Metabolized, and What the Effects and Results of the Metabolism Are

For most people reading this site, elimination metabolism is what pharmacokinetics is all about. How a drug is metabolized in order to be eliminated / cleared from your body. If and how it is transformed into something else and what that is. How it affects the metabolism of other meds6 (see below). To what extent everything is involved. E.g. by the time your liver and kidneys are through with it, 97% of Paxil (paroxetine HCl) has been converted to inactive stuff that gets flushed down the toilet, whereas 70% of the Topamax (topiramate) you take is unchanged in your urine. See the section on CYP450 and UGT enzymes on the Pharmacokinetics page for more details.

3.1  Elimination Method

Enzymatic hydrolysis. Specifically those in the acetamide group. Very few other drugs and prodrugs are metabolized or transformed, wholly or in part, via enzymatic hydrolysis. What few we can find include things like the anticancer med raloxifene and numerous protease inhibitor prodrugs.

Does this have something to do with why Keppra works so well with brain tumor-induced epilepsy? Who knows. It’s probably just coincidence.

3.2  Transformation Method

3.3  Active Metabolites

None so far.

The pill you take is not necessarily the drug that actually does something. Trileptal, Effexor and Risperdal themselves don’t do squat, but are each transformed into active metabolites that do the real work. Predigested versions of Risperdal and Effexor are now available as Invega and Pristiq. Other meds, like Wellbutrin, do something and are transformed into one or more active metabolites that also do something.

3.4  CYP450 or UGT Enzymes levetiracetam Inhibits/Induces/Suppresses

We try to list CYP/UGT/etc in descending order of extent. The first one that does the most of the work, the last one does the least7. That’s how it is on most PI sheets these days.
Nothing. Absolutely nothing.

4.  Drug-Drug, Drug-Supplement, Drug-Food Interactions

Most drug-whatever interactions involve elimination metabolism. With crazy meds the best known example is Lamictal and Depakote or whichever flavor of carbamazepine you’re taking. If you’re taking Depakote you need to take less Lamictal less often. With Tegretol or Equetro you need to take more Lamictal more often. That’s not always the case. Interactions can affect transformation, which is why Paxil + tamoxifen = that breast cancer isn’t going anywhere, because tamoxifen itself doesn’t do shit, your liver turns it into endoxifen (and perhaps others), which does all the dirty work. Interactions can also be potentiations, where one drug enhances the effect of another without slowing its clearance. All patient information leaflets and drug-drug interaction checkers have boilerplate potentiation interactions along the lines of, “two or more antidepressants meds can make you extra drowsy/spacey/ready to go on a tri-state multicide spree.” Alcohol potentiates the sedative effects of TCAs, while alcohol and benzodiazepines potentiate each other8. There can be interactions that are beneficial, and those rarely show up in PI sheets or drug-drug interaction checkers.

4.1  Noted Drug-Whatever Interactions

Not a damn thing, which is noteworthy in of itself. This study suggests that maybe there are some in a few people, but the data aren’t clear and the differences are too small to matter.

Practically every other med will interact with something else, because even if they are just substrates of (are metabolized by) the same CYP450 or UGT enzymes there can be competition. Even Neurontin is self-inhibiting - take too much and you’ll get less and less out of it. But it just doesn’t work that way with Keppra.

And until its derivative, or the other med based upon it, hits the market, there isn’t much in the way of pharmacodynamic (what the meds do in your brain) interactions because Keppra works in a way that is truly unique.
Only one pharmacodynamic interaction has been reported when combining Keppra and Tegretol (carbamazepine). Mixing the two can cause the symptoms of taking too much Tegretol, even though there is no change in blood levels. This may or may not have something to do with this odd thing of one-way cross-tolerance in rats given Keppra and Tegretol. So if you are taking these two meds there is a small chance you may need to reduce the amount of carbamazapine you take, or stop taking whichever one didn’t work as well for you.

4.2  Check for Drug-Drug-Drug Interactions

Drugs.com’s drug-drug and drug-food interaction checker


5.  levetiracetam Bioavailability and Bioequivalence Data

Bioavailability is what PK is really all about. How well a drug is distributed through your body after you take it is important to understand for two critical aspects of pharmacology: these are the numbers a generic manufacturer has to meet for a drug to be considered as bioequivalent; and they help to explain why the raw numbers you see on the SSRI/SNRI equivalence page don’t seem to add up.
If these data aren’t entered, look them up in the pharmacokinetics section of the PI sheet. These data are usually in the US PI sheets - almost always for newer meds, less often in older ones. You’ll also find a wealth of information at Japan’s Pharmaceuticals and Medical Devices Agency site. These data are now appearing in more and more PI sheets / specifications of product characteristics (SPCs) from other countries.

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Doses/dosage affect on PK: Dosage Proportional9
Plasma elimination half-life (T1/2): Keppra XR: 7 hours. Keppra IR: 6–8 hours.
Estimated plasma clearance (CL/F): About two days.
Time to reach steady state & conc. (Css) in ng/ml: 2 days
Time of maximum plasma concentration (Tmax): Keppra XR: 4 hours. Keppra IR: 1 hour
Peak plasma concentration (Cmax) in ng/ml:
Area under the curve (AUC0–24), as ng.hr/ml:
Overall bioavailability (F)%: 100
Protein binding%: 10

6.  Comments and Miscellaneous PK Data:

AKA whatever additional help with your homework we can provide.
Eating a high fat, high calorie breakfast before taking Keppra XR delays Tmax by 2 hours and increases Cmax. Doing the same with Keppra IR delays Tmax by 90 minutes but decreases Cmax.

IV PK data for TBI:
half-life 5.2 ±1.2 hours, systemic clearance 5.6 ± 1.8 L/hour, and volume of distribution at steady state 36.8 ± 6.3 L.

IV PK professional lab rats:
The pharmacokinetics of LEV administered by IV infusion was comparable across all dose groups and infusion rates. Respective geometric means (coefficient of variation) for 4,000 mg administered over 15 min and 2,500 mg infused over 5 min were maximum plasma concentration, 145 (24.6%) and 94.3 (36.2%) mug/ml; area under the plasma concentration-time curve, 1,239 (19.2%) and 585 (9.6%) mug/h/ml; terminal half-life, 8.0 (14.5%) and 7.0 (12.7%) h.

More IV PK: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3002622/

All sorts of PK info at: GlobalRPh’s PK Tools

One more thing - because you usually piss away 70–100% of the remnants of anything you take10, and almost all crazy meds (and all medications in general, including OTC drugs) affect and/or are affected by your liver, if you have a problem with either or both of your liver and kidneys, most, if not all of this information is going to be very different as far as you’re concerned. We can’t cover everything. The PI sheets usually have as much generic information as possible, but there is still a lot of individual math involved. E.g. the Topamax PI sheet gives lots of hard data about how its rate of clearance changes if you have kidney problems based upon creatine clearance and what sort of dialysis treatment you’re undergoing, written in the language of nephrologists. You could bring the PI sheet to your kidney specialist, point to that section, and the doctor would probably be able to tell you how much you’d need to adjust your dosage by. But in the very next paragraph:

Hepatic Impairment
In hepatically impaired subjects, the clearance of topiramate may be decreased; the mechanism underlying the decrease is not well understood [see Dosage and Administration (2.7)].--Topamax Full US Prescribing Information

And that’s it. So if you have liver and/or kidney problems, you’ll need to talk to your pharmacist, your doctors, and, if possible, try to get your doctors to talk to each other about it.

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7.  References

  1. Poore, Jerod. “Lamictal (lamotrigine): a review of the literature and consumer experience. Highlighting its use, adverse events, and pharmacology from the educated consumers’ perspective.” Crazymeds www.crazymeds.us (2014).
  2. Ma, Margaret K., Michael H. Woo, and Howard L. Mcleod. “Genetic basis of drug metabolism.” American Journal of Health System Pharmacy 59.21 (2002): 2061-2069.
  4. McHugh, Josh “Drug Test Cowboys: The Secret World of Pharmaceutical Trial Subjects” Wired Magazine 15.05 (24 April 2007) Revised 10 May 2007
  5. Keppra (levetiracetam) Full US Prescribing Information
  6. Lynch, Tom, PharmD, and Amy Price, MD “The Effect of Cytochrome P450 Metabolism on Drug Response, Interactions, and Adverse Effects” Am Fam Physician. 2007 Aug 1;76(3):391-396.
  7. Le, Jennifer, PharmD, MAS, BCPS-ID “Pharmacokinetics” Merck Manual for Healthcare Professionals Last revised May 2014
  8. Pharmacorama’s Pharmacokinetics section


Consumer Reviews & Comments | Keppra Index | Mechanism/Methods of Action/How it Works

1 Pharmacokinetics literally means how a drug moves through your body, (from the Greek pharmakon - medicine, and kinetikos - to set in motion) and that is exactly what it's about. From the time you swallow (or however it's delivered) a med until you piss it out (which is how most of the remnants of most meds finally leave).

2 However, the FDA requires only a single, frequently sub-therapeutic dose taken by healthy volunteers - who are mostly, sometimes entirely white males between the ages of 20 and 50 willing to take recently developed drugs because they need the money - to determine pharmacokinetic data, including bioavailability and bioequivalence factors.

3 Based on Julien's calculations from A Primer of Drug Action, the half-life multiplied by five is the generally accepted estimate of how long it takes a med to be eliminated from the blood stream/plasma of someone with a normal metabolism.

4 Or whatever. Metabolization, usually via the liver is just one part of process of how a drug is eliminated from your body. Not all drugs are metabolized, but as it's the best-known way many crazy meds are broken down to make it a lot easier for you to piss or push them out, I'm sticking with the less-than-accurate terminology that I've been ignorantly using for nine of the last 10 years.


6 AKA 90% of drug-drug interactions.

7 The last ones listed may not do anything at all, as the data about such things are often conflicting.

8 Or: Alcohol + TCAs = Die like a 1960s trophy wife. Alcohol + Benzos = Die like a rock star.

9 The PK of some meds is affected by the dosage (how much you take, e.g. Cymbalta), or the number of doses (how often you take it, e.g. Lamictal). If it's blank then we don't know. Otherwise:
* No: Dosage / Number of doses doesn't matter
* Dosage Proportional: How much you take affects the PK at a steady rate.
* Dosage Non-liner: The dosage affects the PK, but how it does is complicated, or makes no sense at all.
* Number of Doses: How often you take the med affects the PK.
* Other: There's an effect that isn't like any of the above.
* Unknown: We know that they don't know if there's an effect or not.

10 There are always exceptions. With Geodon you crap out 66% of the inactive stuff it's converted to for elimination, and with Latuda (lurasidone) you crap 80% of its leftovers. So anyone who calls Geodon or Latuda "a shitty drug" is a lot closer to the truth than they may realize.


Last modified on Thursday, 26 September, 2013 at 17:53:32 by JerodPoorePage Authors , Jerod PooreDate created Tuesday, 04 October 2011 at 11:12:28
Citation options to copy & paste into your article:
Linked: <a href="https://www.crazymeds.us/pmwiki/pmwiki.php/Profiles/Kassiane S">Kassiane S</a> and <a href="http://scholar.google.com/citations?user=5rkux7sAAAAJ&hl=en&oi=sra">Jerod Poore</a>. <a href='https://www.crazymeds.us/pmwiki/pmwiki.php/Meds/KeppraPharmacokinetics'>"Keppra (levetiracetam): a Review for the Educated Consumer."</a>. <a href= "https://www.crazymeds.us/pmwiki/pmwiki.php/Main/HomePage"> <em>Crazymeds (crazymeds.us)</em></a>. (2011 ).




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