78. PK: Pharmacokinetics summary

One PK table to rule them all
One table to find them
One table to bring them all
And in the darkness blind them…

…with awesome antibiotic PK facts you can use to bedazzle your friends and enemies alike!

Prep notes here. 

Transcript

PK summary

Callum: [00:00:00] Of the great pharmacokinetic tables. One was given over to absorption, that the wisest and fairest of all doctors could use highly bioavailable agents. Another to the lords of distribution, great craftsmen of dosing regimens. Transcribed lastly, elimination was gifted to the race of pharmacists who above all else desire prompt excretion.

For within these tables was bound the strength and will to prescribe antibiotics correctly. But they were all of them deceived, for another table was made. In the land of morons, in the fires of Mount Notion, the dark lord Jame [00:01:00] forged in secret a master table composed of all others. One table to rule them all.

Jame James, Sauron didn't laugh.

Jame: All right, just play the theme tune, Callum.

Callum, how are you doing?

Callum: I'm feeling Galadriel to see you.

Jame: Well, that's good actually. That's a surprising difference from the norm.

Ah, 

Callum: This is our Lord of the Rings themed episode. Oh wait no sorry. Farmer Kinetics.

Jame: Farmco Kinetics, our favourite thing in the world. And here I've got for you Callum, a thing of beauty.

Callum: Jame has, a fur child. 

Jame: One that I love. just as much as the other two, let's say no more than that. but yeah, I've taken all of the stuff that we've been talking about over the last [00:02:00] three episodes and I've smooshed it all together into one antibiotic pharmacokinetics table to rule them all. 

Callum: So, James, we've just done three episodes on Pharmacokinetics, which is your favourite subject and I just wondered if people haven't listened to those last three episodes, why not? Then what is it that we've summarised here? What are we talking about?

Jame: So we're talking about the pharmacokinetics of all antibiotics that are in common use let's say in the UK and, you know, to a lesser extent in, in, in Europe in general. And this will be of use to people who are working in, in, you know, comparable healthcare systems. And we've You know, we've had episodes on absorption, distribution, metabolism, and excretion, and I've got the data as far as I could get it from those three tables, and I have smooshed them together into one one table to rule them all.

And so starting with absorption, [00:03:00] distribution, protein binding metabolism, excretion, clearance and half life for every antibiotic that is available in the UK. Yeah, so I've kept the traffic light color coding for bioavailability and then hydrophilic versus lipophilic.

And then the rest of it, there's not a lot of color in it, to be honest with you,

but Yeah.

Callum: yeah.

so what's the purpose of why have you done this?

Jame: Well, eight, you know, I am mindful that the Previous three episodes, this data has been presented in sort of multiple different tables in the prep notes, and we've discussed them separately. I thought it would be good to actually have it all available in one place as a reference. And I've also got, down there at the bottom, a copy of the table as an Excel spreadsheet for download. So if you want to steal this and modify it according to your own wishes, then you may do so. And the link to do that is in the prep notes for this episode.

Callum: Instead of a dark lord, [00:04:00] you could have a queen, dark and terrible as a knight.

Jame: Indeed you could Callum. Treacherous as the sea. Ah, yeah, I've seen the movies. But yeah. The You know, the purpose for it is to use as a resource for, , other people so that they can improve their knowledge about the pharmacokinetics of these drugs and therefore , how they're best used.

Callum: It's very helpful of you. Thank you. I am going to use this table.

Jame: Are you? You're going to use it to win fights.

Callum: Fight! Nerdiest fight in the world! I would never have a fight. But, 

Jame: Indeed. But if you did, this would be very

Callum: I might use it in, in, in in discussions. I 

Jame: polite discussions with colleagues, yes, I'm sure.

Callum: You're making me sound like some sort of tyrant. So the table has got a lot of useful information in it. And as James says, we all the way back. A couple of months ago started talking about from a very [00:05:00] basic level about how to choose an antibiotic and this becomes very complicated very quickly and I'll admit that there's some stuff that we've discussed in the last couple of episodes that I do struggle to get my head around.

Understanding it, although this is quite complicated, it does sort of help when you're thinking about using antibiotics, thinking about, you know, maybe why. I was recently reading the BIA meningitis guidance, which is really great resource and well laid out. And one of the, one of the questions I had reading it was why.

Keftraxone, like in the UK, certainly in lots of places, someone presents with meningitis. Everyone's, you know, you, everybody, I think almost every doctor in the UK would know that you treat meningitis with Keftraxone. It's so embedded in our practice. And then it got me thinking why is that the drug?

And going back to some of the literature and Cochrane reviews of Keftraxone versus older [00:06:00] therapy options like Amox or Menpen and chloramphenicol but there's not that much like clinical data, but there was a line in the BIA guidance and it talked about this is recommended based on the pharmacokinetics.

Jame: Oh yeah. Thank 

Callum: really interesting. I was like, whoa, because I guess sometimes we practice medicine in a way that is like guidelines say jump. So I jump. Yeah. But when you dig into where there isn't data, I think a lot of the times things are leaning on pharmacokinetics and that is the basis by which we practice.

Like if you're not, if you're in an area where you don't have a clinical, you know, I think nobody would disagree that a randomized controlled trial is well conducted as the highest form of evidence and that's what you'll base your treatment decisions on. But, you know, if you're in an evidence free area, then this is what you're going to come back to.

Back to, isn't it? It's the pharmacokinetics.

Jame: Yeah, if you know it.

Callum: Well, you're about to find out.

Jame: Wow. Will we go through some of the winners and losers, Calum?[00:07:00] 

Callum: Yeah, so I guess not everybody will have the table in front of them Recommend, if you go on to your podcast player choice in the show notes, there'll be a link to Notion page, which is a sort of website that James has been putting lots of lovely show notes on. And in there you'll find the table, and really, Recommend if you're driving, maybe after your journey, if you're doing something else, just have a wee look at the table and maybe come back to it later on.

So yes, we've got some things to pick out when we're talking about pharmacokinetics of different drug classes

Jame: yeah, so I think first we need to, I've sort of divided this into highest and lowest and let's start with bioavailability. So the our highest, most bioavailable drugs are Levofloxacin and Linezolid, which are functionally 100 percent absorbed. Our lowest are Phosphamycin and Erythromycin, which are about, you know, a third. Each in terms of bioavailability, so not very much there. This is good knowledge, I feel, because that makes me increasingly [00:08:00] doubtful of the utility of giving IV linezolid. Say to anybody whose oral route isn't compromised or they don't have septic shock.

Callum: really ever given that.

Jame: Well, when people are thinking about Using linozolid.

I think some people would still Start IV and then oral switch

and I'm more and more of that idea Yeah If you were using see for example, you were using it in them you were replacing clindamycin with linozolid in necrotizing fasciitis

Callum: Open that can of Worms, man.

Jame: Yeah, exactly. So there's a

big position paper about that came out a few months ago, and I think, actually, in that case, if you've got somebody who's got NECFASH, fine, get it in IV, first couple of doses at least. After that, post opsy assuming that they've been taken to theatre and debrided, I'm not sure what good that's doing unless you actually think that the gut is compromised. And [00:09:00] certainly if you're using it for a severe cellulitis or even a cellulitis with shock, but they don't have neck fash as long as their mouth is working, I think it's perfectly okay to give it.

Callum: I think I would go further and say, you know, in that sort of situation, you know, you're probably giving quite a few different drugs and there's a lot going on. At the time, you know, you've probably got limited access, you may be giving a co oction or different antimicrobials. I'd just give the linizolid orally and get it in, get it started working quicker.

Jame: Yeah. Yeah. 

Callum: how long does an IV infusion take?

Jame: Well, indeed. And you could actually co administer a highly bioavailable oral drug with IV as well, and some would argue that would be better. Yeah. And then the other thing I'll point out is that the erythromycin, the, this is a bit of a historical thing, Callum, but that bioavailability and combined with pretty high volume of distribution. The early endocarditis management was done with penicillin and that [00:10:00] got about 70% success rate. And as a reminder, endocarditis was 100 percent fatal, functionally before the introduction of antimicrobials. People tried, uh, sulfonamide antibiotics as well so cousins of sulfamethoxazole, but they have pretty high MICs to the target organisms. streps and staphs. So they very quickly were like, that's not very useful. And then they moved to macrolides. They tried to treat endocarditis with erythromycin and they got a like 25 percent success rate. And they were like, that's not nearly as good as penicillin. And so we're just going to stick with penicillin.

Callum: It must be because erythromycin is bacteriostatic, that must be the reason.

Jame: Don't even get me started Callum. But that, What I just discussed is the only evidence in the literature for oral being inferior to IV, that anecdotal data comparing penicillin IV with something that has high [00:11:00] MICs against the target organism, or something with a high volume of distribution that doesn't get good plasma levels. That's the only, and even then it had a 25 percent success rate.

Callum: this is kind of crazy it actually worked at all, isn't 

Jame: This is infuriating. But anyway yeah, it is crazy that it worked at all. And, you know, I'm certainly not suggesting that we use macrolides for endocarditis now. But that is the only evidence for IV being superior to oral, and I think you, I'm sure you could agree that's pretty shoddy evidence, and just about every observational study, case series, and four RCTs and counting providing evidence, you know, just in the field of endocarditis, I'm not talking about anything else, that orals are non inferior to IVs.

So next we have protein binding, and it will be no surprise that our number one is dalbovankin. 93 to 99 percent protein binding. It's highly protein bound. [00:12:00] And as a reminder, only the free component is active, but only the free component is excreted as well. So if you give 1500mg of dalbovankin, you know, 96 percent of that will be stuck to albumin, and then the remaining 4 percent will be having the effect on the target organism, and getting peed out at any one time, and this contributes to its very long half life.

Callum: Yeah, that's pretty long, isn't it?

Jame: Yeah and then our lowest would probably be amikacin with 0 to 11 percent protein binding, and the aminoglycosides in general are not very protein bound, which sort of explains why they're quite toxic. Because they're, there's virtually no component, if they're floating around in plasma, there's virtually no bit of the drug that's not free to bind to the target organism and might explain why they've got concentration dependent killing, as opposed to say, you know, time over MIC, which you would get with the beta latibs.

Callum: But if you're saying that's because of the low protein binding, what about [00:13:00] meropenem, which is very lowly protein bound at 2%?

Jame: Yeah, I mean, the protein binding meta was quite low certainly compared to ertopenem which is we've discussed before is quite high, over 85 percent protein bound. And that means that in low albumin states, more of the dose that you give will be excreted in a shorter period of time.

And people have hypothesized that this has led to erythropenin failures in the intensive care population.

Callum: So that's high and low protein bounding. What about volume of distribution? And

Jame: Well, you've mentioned on the on the relevant episode that Azithromycin is the runaway winner there with a volume of distribution of 2,177 liters. So virtually none of that is staying in the plasma. It's distributing out to the tissues and into the intracellular space. And then the runner up is TIG Cyclone with a VD of about 500 to 600. And then the well, not losers, but just, you know, this is [00:14:00] just they just don't want to leave the plasma particularly would be a Keflexin with a VD of 5. 2 to 5. 8. Liters and daptomycin with seven 

Callum: so thinking about daptomycin for just a second as a drug in itself. So this is a drug that's highly protein bound at 90 to 93 percent and has a very low volume of distribution at 7. And I was rereading the Infective Endocrinitis Guidance , I guess that, you know, that sort of combination there makes me think, Oh, that'd be good for intravascular infections. It kind of makes sense that might be a good, you know, thing to use against your infective endocarditis.

Jame: And low rate of clearance as well. Presumably because of the high protein binding. But, and the all this is true Dabba van as well. You see that they sort of follow each other through these tables. 

Callum: Yeah. But

DBA for,

Jame: very low at 0.9 Mills a minute.

Callum: I guess we just don't really have the data yet to support that. But, 

Jame: Yeah, well, I mean, I'm sorry. I'm not suggesting that we'd use it for [00:15:00] endocarditis. Not for nothing. It's a glycopeptide, so it's definitely not my first choice endocarditis treatment. But yeah. But they're, they sort of are very, pharmacokinetically are quite similar to each other.

They've got high levels of protein binding, low rates of clearance, and daptomycin vary has a very small volume of distribution. Let's see.

Callum: so, just going onto clearance as you mentioned it. So, kind of continuing the theme. So if CIN is very highly cleared at 6, 630 mils per minute, and our lowest level is dalbavancin at 0.9, I don't think there's any surprises there. And then half life. So again, on one end we've got Dalbovance in the highest half life at 346 hours. And interestingly, azithromycin isn't the lower end, so it is actually got a really long half-life at 68. So I guess you can contrast there, the halflife of Dalbavancin and the half-life of Azithromycin, which are very different pharmacokinetics.

And they very different reasons. So, Davanon's half-life is very long because it's highly [00:16:00] pro bound to the protein. and just doesn't get cleared because there's not the sort of free drug ready to be cleared. Zephyromycin is a very long half life because none of it's in the serum to get cleared. It's just not there.

So it's kind of having to diffuse, it diffuses out into tissues and then slowly comes out the tissues back into the serum which allows it to be cleared.

Jame: Yeah. So there's two ways that you can have a long half life. One is by being very highly protein bound and very little of you is free in the plasma. And the other is that you can leave the plasma altogether. And so the dabavankin and mezithromycin are two examples of that strategy, if you can give a drug a strategy. To have a long half life, yeah. And then the lowest half life drugs are, it will come as no surprise, penicillin. Is our number one. An average of about half an hour. So this is why you have to dose penicillin if you're using it so many times a day. To the frustration of the administrator of the drug. And why a lot of people would [00:17:00] default to amoxicillin, which has a longer half life of about an hour, which means you can give it four times a day. Or so for a serious infection and not annoy the nurses quite so much.

Callum: Yeah, so that's some outliers. Maybe to finish we could just take one drug and go all the way through its journey in the body.

Jame: Well, I think we should use just as an example, maybe Cotamoxazole. Yeah, down at

Callum: Okay, I'm happy with that.

Jame: the bottom. Yeah, so what I've done then is I've sort of tried to summarize the characteristics of each antimicrobial by drug class, so starting with the beta lactams and going down to the antifolate drugs at the end just to give people a very kind of rough idea, and I sort of talk about their absorption, distribution, metabolism, excretion, and half life, but maybe just as an example, we'll talk about cotrimoxazole the antifolate drugs.

Thanks. Yeah, Cal?

Callum: Yeah, so we'll just take you on a journey. I don't know, this is gonna be a very niche reference that most people probably won't get, but there was this [00:18:00] amazing program and turned into a game called the Magic School Bus. 

Jame: At this point in the episode, Calum started talking about a magic school bus TV show that I'd never heard of and that I'm not sure anybody else did. So instead, just think about that episode of Rick and Morty where they go inside the the person and they explore the

body and it's been made into a theme park.

There we go. 

Callum: that's a reference to it. I actually just Googled the game and I found a way you can play it online for free. So I guess I know what I'm doing, 

Jame: Heavens. All right. All right.

Callum: learning about the human body. So, 

Jame: Yeah. So cotrimoxazole is an interesting one because it's got two components. Trimethoprim molecular weight, 290 Daltons and sulfamethoxazole, 253 Daltons. Now, luckily enough, both of them are very similar. reasonably lipophilic and reasonably bioavailable. So greater than 90 percent absorption for both of those. 

 And then in terms of protein binding, [00:19:00] they're very similar, sort of 44 percent for trimethoprim, 70 percent for sulfamethoxazole, so you would call them sort of medium protein binding, and their volume of distribution is 13 litres for sulphur and 25 for trimethoprim. So again they're not all that far away from each other in terms of where they're going and what they're doing. So they're, if you think about the The, our 70 kilogram male Callum, 13 litres is not all that much more than plasma assuming that you've got about three and a half to five litres of plasma within you.

Jame: So it's not leaving the plasma all that much. And the same with trimethoprim, VDF25. Again, it's not It's what, maybe a third of your of your body weight. So it's mostly staying in the plasma. In terms of metabolism, they are both metabolized to inactive metabolites by CYP two C nine, and Ethin by CYP [00:20:00] three A four.

So this is one that metabolizes most or 60% of all drugs and they're excreted renally 55% for trim and. 85 percent for Sulfa and this is good as far as we are concerned for treating UTIs because it then means that you get these massive levels and because Cotrimoxazole's PD parameter is is AUC over MIC, you'll get lots and lots of kill with Urinary Tract Infection. Clearance of 50 to 90. And 20 mils per minute, respectively. And then half lives very similar, 8 to 10 hours for each.

Callum: It's quite long. Oh,

Jame: allows, that's what allows for sort of BD dosing. Is that long half life and the, if you compare to other stuff. So once you get above 10 hours, you can tend towards once a day dosing. So for example doxycycline's half life is 12 hours. [00:21:00] So if you're a sufficient dose. Number above the MIC of your target organism. So say you load with 200 milligrams and you'll get a plasma level of about, say four. Well, your, the MIC of of strep occi against doxycycline is sort of, for a lot of them it's one. So if you think, if you're going from four, one half, life will get you to two another, half life would get you to one, and then you would dose them with another a hundred milligrams. You know, and so then you're back up again to, you know, three or four or something like that. And so you can stay above the MIC almost definitely. So that's the explanation why with DOCSI you would do a 200 milligram load and then give 100 milligrams once a day. Depending on your trust, you might be giving 100 milligrams twice a day. And so then you're giving 100 milligrams every day. 12 hours, which is only one half life. So functionally you'll be permanently above the MIC for the whole [00:22:00] course if you do that.

All right, so NADOS Royal Infirmary South does that. Mostly because we can't get the our e prescribing system to play nicely with the 200 load and then the 100 on days 5. But yeah, So

like once your half life is, you know, that high, it sort of depends on what your PD target is.

You know, for Beta LatTimes, if your time over MIC target is 40% you may you know, get away with two or three times a day dosing with say, you know, Peptaz. But say, if you're treating a Pseudomonas, your PD target is 60 to 70%, you would need to move up to four times a day. And that's the, that's why Peptaz is dosed four times a day for Pseudomonas.

Callum: all these, this pharmacodynamics stuff that James talking about. So we've just done a mini series on pharmacokinetics. And I think often when we talk about this, we say PK and PD, and then we don't really talk about it more. So I think there will be a mini series on pharmacodynamics coming up, but we're going to do [00:23:00] something else for a bit before, before we do that, please.

Jame: Okay, fine Callum. I heard you loud and clear. You want a break, but it is coming.

Callum: It is coming. So we'll come back to pharmacodynamics, , so that's a worked example. So, you know, I guess we've gone through the table.

We've given you a couple of top trumps and James has neatly summarized it and given us in the show notes, some just some reflections on the different drug classes and what they mean. And I guess the way I think I'm going to use this as a listener is I'm going to When I'm thinking about, you know, drug options or complicated situations or things outside evidence areas, then I'm probably going to come back to this and use it to, to think about part of my sort of thought process, I guess, about how to choose an antibiotic.

Jame: Yeah, good. And that's how it's intended. I think certainly as a clinical pharmacologist, I've been wanting to create something like this table for years, just to kind of, like, get it all in one place, because the [00:24:00] trouble is that all this data is spread across SPCs and, you know, you can look up individual drugs in, you know, in drugbank.

ca, for example, and, you know, UCAS has some brilliant documents on on these drugs and, you know, wherever possible, I've tried to pull the PK data from there, particularly the bioavailability and half life data, but, you know, at the end of the day you were always able to access individual drugs, but actually getting all of them together was like a major hassle. And in fact, looking back on this project, I should have just made this table and then talked about the individual components because it didn't do that. I made three different tables and then I smooshed them together. I probably shouldn't have done that.

Callum: I think it's, I think it's quite a complicated subject, so I found it helpful to, to sort of split it up into bite sized chunks and then put them together. Like laptime ring. So

Jame: Yeah. Just so that's exactly [00:25:00] the analogy I was about

Callum: I guess now we've got, James, we've got your one table to rule them all. After we've had our one James finding all the data from all over the internet and bringing them all and binding them together.

Jame: Am I meant to agree? Yes. Yes.

Callum: Yes. Thanks, James, for all your hard work on this and I'll certainly be using it in my practice.

Jame: Thanks, Calum. Thanks for doing absolutely nothing for this entire mini

Callum: Oh, what?

Jame: right. See you next week.

Callum: What?