Pharmacokinetics: Dosing Wars

Pharmacokinetics: Dosing Wars

Editor's Note: It is great pleasure that we introduce Stephanie Kujawski, PharmD, BCPS. Stephanie has agreed to write a pharmacokinetics review series for your tl;dr enjoyment. This is the first installment of that review. Stephanie is an outstanding teacher, preceptor, and pharmacist. She also (for some reason) is very passionate about kinetics. And Star Wars. She really likes Star Wars. Anyway, we'd like to thank Stephanie for writing this very useful review. Enjoy!

 

Episode I: The Kinetics Menace

So, you’re a second year pharmacy student sitting in pharmacokinetics class. You're listening to your professor animatedly discuss this strange new topic. But let’s be honest, you’re still trying to figure out what the word "pharmacokinetics" (or even regular "kinetics") means. 

Frankly, you’re just excited to have a new super long word to use when playing hangman with your classmates. We get it, we’ve all been there. Maybe some of you are STILL there even though you’re finishing up residency or fourth year rotations. Better to understand late than never!

This pharmacokinetics series is going to break down the concept of kinetics for you in a way that will make it more manageable and methodical.  Let’s start with some definitions. 

  1. Pharmacokinetics is what the BODY does to a DRUG.  It includes processes like absorption, distribution, metabolism, and excretion. You probably already know these as ADME.
  2. This is in opposition to pharmacodynamics (another super long word that who on earth actually knows what it is). Well, to make it easy, pharmacodynamics is what a DRUG does to the BODY.  This includes concepts like receptor binding and the downstream effects of that process.

So forget all of the fancy math for a second. This is the essence of pharmacokinetics....

Bacteria Party (Image)

Bacteria Party (Image)

Your professor is using those gibberish math equations (don't worry, we'll get to those...) to describe how a drug travels into and through the body. And then how it eventually gets out. All of this is important when trying to determine what dose to give a patient.

What if we give a dose while the previous dose is still trying to exit? Is that going to overload the system? Or what if those grimy bacteria are partying in between doses because the last antibiotic dose already left town and the next hasn’t yet arrived? 

We, the pharmacists, are trained to predict when these things will happen. Both for particular drugs and for each and every individual patient! Tall task, you say? Well, you’d be correct.  But let’s break it down some.

 

Types of Kinetics

There are a couple different types of kinetics. 

First, there’s zero order kinetics. This is also described as nonlinear or dose-dependent

We won’t spend too much time on zero order, since it’s less common in our day to day pharmacy life. However, you should know it because it usually crops up in phenytoin test questions. Alcohol is also eliminated via zero order kinetics. 

The key point is that it refers to a constant AMOUNT of drug being eliminated over time. It is usually due to the elimination processes in the body being saturated (you've probably heard the term "saturation kinetics"). 

Let's make an analogy. Maybe you have a clothes-buying habit. You can't help yourself. It was on sale! And you got 20% off your first purchase because you applied for the store credit card! Anyway, now you've got too many clothes. Your closet is practically bursting at the seams. 

So you enlist the help of your friends to downsize your closet. Those clothes are soooo-out-of-fashion anyway. #LastSeason. But your friends have their own closets to worry about. They will only agree to take 1 piece of your clothing a week off your hands. So you've got a few friends each taking one piece of clothing per week. 

Meanwhile, you're still buying clothes (What? Nordstrom had a sale). You've got new clothing coming into your closet faster than your friends are taking it out. What do you end up with? A busted closet. 

I have nothing to wear (Image)

I have nothing to wear (Image)

This is the same concept as zero order kinetics.

So in a nutshell, changes in dose (you continuing to buy more clothes) do NOT produce proportional changes in serum concentration (how much stuff is in your closet), which is why plots of dose versus AUC/concentration are curved:

 

It's time to admit you have a clothes buying problem

It's time to admit you have a clothes buying problem

 

First Order Kinetics

Alright, so now that we’ve got zero order kinetics under control, on to the next (and more common) beast. This is first order kinetics. You also know this as linear kinetics. In first order, a constant PROPORTION of drug is eliminated over time (remember from above, zero order was a constant AMOUNT).  What does this translate to? Changes in dose produce proportional changes in serum concentration. 

Let's go back to our discussion of your horrible shopping habits (hasn’t somebody told you to budget???). In this scenario of first order kinetics, your friends would be willing to take 25% of your unwanted clothes each week. Whether that means 5 shirts or 20 shirts, they’re going to take them. 

You'll get rid of your clothes a lot more effectively this way.

True, your closet may indeed one day bust since you’re still buying clothes (you hoarder, you). But it will take a lot longer than in the zero order case. The contents of your closet will gradually, steadily increase until it can’t hold anymore. Plots of dose versus AUC/concentration for first order kinetics are linear: 

Better...but you're still eventually going to break your closet

Better...but you're still eventually going to break your closet

 

Applied Pharmacokinetics: Antibiotics

To quickly recap. So far we've learned that pharmacokinetics describes what your body does to a drug. And that there are 2 common elimination processes (zero and first order) that your body uses to get rid of drugs. Neat. Why does this matter? How do we apply this?

To illustrate, we're going to go back to our old friends, antibiotics. As pharmacists, the bulk of our daily kinetics work involves antibiotics. Remember that these little microbe fighters are broadly divided by how they actually kill bacteria (time vs concentration dependent). 

So let’s look at how we use kinetics to determine our dosing strategy for both time and concentration dependent antibiotics. (I promise, we’re setting up to talk about vancomycin dosing…eventually).

Editor's Note: For a general review of antibiotics (bugs/drugs, renal dosing, kinetics, NAPLEX fodder), check out our quick and dirty guide here.

Antibiotics typically kill organisms in one of two ways. On one hand, there are drugs that have to reach a certain concentration (the minimum inhibitory concentration or MIC) for the bug to die. It doesn’t matter how long the drug stays at that concentration, it just has to reach it. 

This is called a concentration-dependent effect. 

It’s like this (sorry in advance for the mean analogy). We all know at least one "toxic" person. When you encounter them, even if it’s for a short time, you just plain feel exhausted afterwards. 

One quick “dose” of them was more than you could handle, and it killed your mood. They're like the Newman to your Seinfeld. 

These people are concentration-dependent mood killers. Just seeing them is enough to get above your MIC and destroy your mood. In the antibiotic world, our concentration-dependent killers are fluoroquinolones and aminoglycosides. And we use kinetics to maximize their concentrations to kill bacteria.

For most quinolones and aminoglycosides, we dose once per day. That way we can get a nice, high concentration in the body and then let it recover until the next dose. Obviously, our dose is limited by toxicity in terms of how high we can actually go (ie. Be ready to do some explaining if you try giving someone 3 grams of gentamicin).

Quick note before moving on....the "traditional" way of dosing aminoglycosides was three times daily. However, most institutions have now adopted a new "extended interval" dosing scheme that is once daily. This maximizes concentration-dependent killing and actually lowers toxicity because there is an "aminoglycoside free" period at the end of the dosing interval. There are still certain patient populations (pregnancy) where you might use traditional TID dosing.

The other way an antibiotic can kill bacteria is through a time-dependent effect.

With time-dependent activity, the antibiotic has to not only reach the MIC, but also stay there for some time. If it doesn't stay above the MIC for a certain amount of time, it's not effective at killing. 

To return to our analogy, this would be like the annoying coworker you have. You can tolerate them for a period of a few hours. But beyond that they start to kill your mood. You just can't handle it. You definitely aren't going to be inviting them out for dinner and drinks after work. The amount of time that you are in their presence is what kills your mood, rather than their presence itself.  (Again, really, I’m not a mean person! It just makes sense this way!).

Drugs that work in this manner mostly include beta-lactams. How does kinetics play a part? We dose them to increase the time the time that the patient is exposed to the drug.  For example, we might infuse a dose of a drug like Zosyn over 4 hours instead of the standard 30 minutes to exploit this time-dependent killing property.

Ok, that’s seriously enough kinetics for now.  Let it all digest and then we’ll come back to it again soon!  Be on the lookout for Dosing Wars: Episode II...Attack of the Vanc.

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