Thank you, thank you very much. Wow, that was a lot of great information so far, wasn't it, y'all? A lot of information to internalize. Hopefully, gonna simplify it a little bit. We're gonna talk about how to dose medicines in liver failure. And I'm with University of South Alabama Children's and Women's Hospital. That's where I practice, my primary practice area in Mobile, Alabama. I have no disclosures. My objectives today is to review how liver metabolism is important in medications, how we're gonna kind of review the Child-Pugh score and talk about some of the challenges with using the Child-Pugh score and why we're wondering whether or not we should. We're gonna assess some of the other potential strategies for dose adjustment in liver failure and provide some recommendations. So I have titled my presentation To Pugh or Not to Pugh? Is that really the question? So currently I have, I was gonna do a poll everywhere but I can't do it here. So let's take a show of hands. How many actually utilize the Child-Pugh score as guidance for dose adjustment? How many use other scoring tools? How many use the package insert recommendations? There's a few. How many use their clinical pharmacist? Oh good, I like that answer. That's the best answer we have. How many are, wait, we're supposed to adjust doses for acute liver failure? Okay, great. I'm gonna really quickly review some of the pharmacokinetics and how liver failure actually affects these kinetics. Starting with, of course, most of us probably here know that pediatric pharmacokinetics are completely different. They're not like adults, we're not little adults. There's so much variability. We have different age differences. We have the neonates to the adults who can be obese. That already complicates the picture. Add on top of that critical illness and we know critical illness also complicates that picture of our pharmacokinetics. We have different fluid balances. We have different things going on. Now you add liver failure on top of this? Can you imagine how complicated that can be? So pharmacokinetics, just a review. It's absorption, distribution, metabolism, and elimination. Absorption, what we're gonna talk about today when it comes to liver failure is oral absorption. Oral absorption involves all of these things. Basically, your gastric pH, your gastric motility, gastric emptying time, some of those hormones that break up things in your gastric hormones, and then, of course, the first pass effect. And this first pass effect helps because it makes some of that orally absorbed drugs bypass oral absorption. It increases, and then this all together leads to bioavailability. So let's talk about the first pass effect. When you swallow a med, it goes into your gut wall, right? Then it uses the hepatic portal vein, takes out some of the meds, and it goes through metabolism in the liver. Some of this metabolism in the liver gets metabolized and eliminated, and that's called the hepatic extraction ratio, the amount that's actually getting extracted from the liver. The rest becomes bioavailable to the body. So the hepatic extraction ratio is actually a measure of the ability to extract a medication. And as you can see, you can have anywhere from a low to a high hepatic extraction ratio. So you can have a low extraction ratio of only 30% to a high extraction ratio of greater than 70%. High extraction ratios are highly permeable, and they're very clearance-dependent on your hepatic blood flow. Low extraction ratio drugs have very poor permeability They are metabolized by the liver, but poorly extracted via first pass effect. So really, the hepatic blood flow does not affect your low extraction ratio drugs. Clearance is thus limited just by the reduced metabolism and not the blood flow. When it comes to absorption with liver failure, as I was saying, other things that get affected are like your GI hormones, any type of structural alterations, GI bleeding, gastric permeability, and all those type of things are also going to affect your oral absorption. This also, what also really disrupts the first pass effect is your decreased hepatic blood flow. Because this decreased hepatic blood flow is thus gonna decrease your overall clearance of those medications. So as I mentioned before, this is most important for your meds with the high extraction ratio. Some of those drugs that have high extraction ratio are listed here below. And as I reiterated, that could increase your toxicity of these drugs. So these are just some examples of drugs with high extraction ratios. And thus, some you might have to worry in acute liver failure. The other thing we're gonna talk about is distribution. That involves your body composition, your vascular perfusion, tissue binding, and protein binding. In liver failure, of course we know that you have increased fluids or changes in your fluid balance due to hepatic dysfunction. All of this could increase your volume of distribution for those medications that are hydrophilic. So we have to remember if a med's hydrophilic or lipophilic in this case too. So if there's less albumin, that's another thing. So drugs with high protein binding are gonna be very much affected by your albumin. If you have less albumin, you're gonna have more free unbound drugs. These free unbound drugs could potentially cause more effect, more toxicity, and those kind of things. Some of your medications with high protein binding, for example, here is your phenytoin and a few of your benzos. Next, the most important pharmacokinetic pathways, metabolism. And we all know, we've been talking about the liver. So the liver's the powerhouse of metabolism. We know that there's phase one and phase two pathways, and these are the different pathways. Phase one is mostly our biotransformation pathway, and it goes through the cytochrome P450 isoenzymes. And then phase two is usually our pathways that detoxify. When it comes to liver metabolism and clearance, here's when we get into a bunch of like equations and things, not that important, but you know us pharmacy people like calculations and equations. So this is when you talk about things like measuring the hepatic blood flow and finding out what the hepatic extraction ratio is of a drug, which could result in your overall hepatic clearance. Hepatic clearance has to do with metabolism and biliary excretion, the intrinsic hepatic clearance, that is. You also have to look at some of your hepatic transporters, because some of your transporters, like these solute carriers, actually are bringing in medications to the liver, and your ABC transporters are actually pushing them out of your liver. So all of these things have to be taken into account when you think about liver metabolism. When you look at overall hepatic clearance, there's an equation, and that does take into account your intrinsic hepatic clearance and your blood flow through the liver. Don't worry anybody, I'm not gonna go over the calculations. Just showing it to you for reference. So things happen. So when we do have liver blood flow, I mean liver failure, we're gonna have a hepatic blood flow. And usually this is gonna actually affect your phase one pathways a lot more than your phase two pathways. Many times, glucuronidation is actually preserved. It takes, because we know that the liver is a very large organ, and it's actually pretty stable, pretty strong, it takes a lot, a lot of damage to the liver before you would see glucuronidation actually fail as well. And the other thing you'll see with liver failure, of course, is the variability in your cytochrome P40 enzymes. So 3A4 actually is usually way more affected by liver failure than your cytochrome P450 2C9s, or 2Cs. And then liver failure can also decrease some of those transporters that I talked to you about earlier. Elimination, we all know that's filtration, secretion, reabsorption, and clearance. With hepatic failure, you might have increased clearance of those unbound medications, so the ones that aren't bound to your albumin and things like that. You're also, of course, gonna have decreased renal clearance because of renal failure associated with your acute liver failure. And then you might have actually increased secretion of creatinine. So what do we do when it comes to drug dose adjustment? Well, guidelines actually recommend adjusting doses to undergo hepatic metabolism. Great, I'm so excited they tell us that. But they actually don't tell us why, or they don't actually tell us how to do it exactly. They don't give as good guidance as like renal failure dose adjustments and how much to adjust by, it's kind of a more global for renal dose adjustments. It's not the same for liver dysfunction. There's actually limited evidence and or guidelines to assist with dose adjustments. And as I mentioned before, you really need significant liver impairment before you really have to look at some dose adjustments and before they're really clinically relevant. The other complication is most of our drugs, we have so many billions of drugs and they all have their own different characteristics as we just talked about with all the different pharmacokinetic parameters you have to look at. So it's really hard to globally say, oh, decrease this by 50% and then these by that. Not to mention that there's so many individual patient factors that have to go and that are involved as well. The other problem is we don't really have any surrogate markers to estimate liver impairment in terms of function, like how well it's metabolizing medications. What we have been using is the Child-Pew score for the most part to, and we're all probably familiar with the Child-Pew score with the one, two, three criterias. The problem with the Child-Pew score is actually your encephalopathy and your ascites is more subjectively determined than objectively determined. The other problem is it only goes up to 15 points and you only have three phases, mild, moderate, severe. FDA guidance has actually pretty much recommended that we use the Child-Pew score since May of 2003. You'll see it in almost all the package inserts. A lot of drug companies are mandated to look at liver dose adjustments based on the Child-Pew score. The Europeans also recommend this as well. However, there are other organizations like the National Cancer Institute, which actually uses a National Cancer Institute classification that's different from the Child-Pew score. They actually did a study too where they reviewed five years of oncology meds to determine whether or not the medication dosings were based on the Child-Pews. And they found that actually 46% of the medications dosing recommendations were based on Child-Pew score. And this is only in oncology meds, but only 8% were actually tested in terms of clinical trials using the Child-Pew score. So there's kind of a dichotomy there. So the question is, again, is it time to revisit the Child-Pew score? The Child-Pew score actually assesses disease severity. It doesn't really assess function or how well that liver metabolizes medication. It is, as I mentioned, somewhat subjective in those two areas. It does not include anything about renal dysfunction. So there's no way to determine that. You'd have to look at it separately. It also doesn't look at the etiology of liver failure. And there's definite variability that's been seen between patients assigned the same scores. So there's questions there as well. The cutoff points are not as well validated, and therefore some people questioning the cutoff points as well. And as I mentioned, it really doesn't correlate with liver metabolic capacity and how well it actually metabolizes medications. There are some other scoring systems that have been studied and looked at and considered. There's the MELD, I'll just call it the MELD, and there's a pediatric version called the PELD. And these are actually simpler tools, scoring systems. Like the MELD and PELD only look at serum creatinine, serum bilirubin, INR, and serum sodium. However, it is really mostly looked at in dialysis patients. The thing that is liked about the MELD and the PELD is the score range is wider and larger. And so some people feel like it actually characterizes the severity a lot better. The National Cancer Institute Organ Dysfunction Working Group has their own classification system, the NCIC, which is the one I was mentioning earlier. That actually only looks at the total bilirubin and the aspartate aminotransferase. Then there's a Madry's discriminant function, and you see the Mayo survival model. Both of those aren't quite used as much, but those are other options. Other people have also thought, well, we might need to look at surrogate markers that tell us how well a liver metabolizes a medication. Some of these markers are listed here. The MEGx, I won't say the whole name, but the MEGx is a lidocaine metabolite, and that's metabolized via 3A4. And because of that, it actually assesses oxidative enzyme activity. However, you have to give lidocaine. It's a little bit invasive. The other, endocyanine green, is also a metabolite that's an indication of hepatic blood flow. Again, this is also something you have to kind of give to your patient and watch. The galactosingle point, it defines the clearance of highly metabolized drugs and drugs without liver metabolism. However, all of these markers so far aren't clinically relevant and really well used at this point, and so they still have a lot to go. Some other potential strategies that have been considered are redefining the child PUS score. There's some people that have actually thought about adding a class D, and are increasing the numbers and having more classifications in there. There's a disease severity index scoring, and some people have looked at CT imaging and said that you can look at how many hepatocytes that you have in cytochrome P450 enzymes, and that can tell you how well your function is. There's a lot of PKPD modeling and simulation that's also been done to look at some of the child PUS scores or some of these other scores to see if the modeling can tell us much better about dosage adjustment. Something I thought was really interesting are the lipid biopsies and multi-omic techniques where they look at the exosomes and determine how well those exosomes are metabolizing in the liver. And then some more simpler strategies that people have looked at is just albumin and bilirubin grade or just the bilirubin alone. There's a couple studies that have been done looking and comparing the child PUS score with other scoring systems. So Curata et al looked at theophylline, and theophylline's a cytochrome P451A2 marker, and they compared the MELD versus the child PUS score looking at the theophylline. In this study, and all these studies, by the way, are retrospective, in this study, they found that the MELD was more accurate for liver cirrhosis and liver function with theophylline in particular. Another study looked at erybulin, which is a 3A4 marker, it's a chemotherapeutic agent, and in this study, they compared just looking at AST, ALT alone versus albumin plus the AST, ALT versus just bilirubin alone. And they actually saw that bilirubin alone was associated with increased toxicities of this erybulin and required dose modifications. Another study looked at 117 different oncology compounds, and this is the one that compared that National Cancer Institute classification versus the child PUE. They also did some PK analysis in there. They found that majority of the meds, three of the meds that they looked at were consistent between the NCI and the child PUE score. One of them, they actually saw that the NCI required a dose reduction where the child PUE didn't, and then another one was the opposite, where the child PUE would have suggested a dose reduction and the NCI wouldn't have. Midazolam is also a 3A4 probe that has been looked at retrospectively, and they compared child PUE versus the MELD in that one. In that case, they found that they were both equal. This is to say that, as I mentioned before, even the studies have a hard time coming to a consensus because all the medications are really different. So the only thing I can say is, I leave you with some general dosing strategies. Avoid meds, of course. They have significant hepatic metabolism, if you can. If there are dosing recommendations available based on the child PUE score, then sure, utilize them. If you don't have recommendations, however, then the bilirubin alone might be a good marker for you to help dose adjustments. The NCI is another one that you could potentially think about using, which was looking at the bilirubin and the immunotransferase. You could assess the hepatic ratios of the drugs that you know, if they're known. You can't always find hepatic ratios on drugs. You always should just, in general, start low and go slow, even in acute liver failure. Serum drug monitoring is encouraged whenever you have it, and definitely you should do it when possible, especially in this setting. Think about the potential pharmacodynamic interactions, and of course, think about your risk versus benefits. Some other questions to ask prior to starting any medications under acute liver failure, is this acute versus chronic liver failure? Does this medication have first-pass metabolism? That goes back to that hepatic extraction ratio. Is your meds highly protein-bound? Do we have to worry about a change in volume and distribution, and will that clearance be altered as well? Are any pharmacodynamic interactions present? The rest of the, a lot of the slides, and if you look in your handouts, are really just a list of drugs. I'm definitely not gonna spend time going over all of them. They're really for your reference. So like some of your high extraction ratio drugs, some intermediate extraction ratio drugs, the ones that have low extraction ratios and low protein binding, low extraction ratios and high protein binding. So basically, you should know your meds. If you, you should think about whether it's lipophilic or hydrophilic, if it undergoes first-pass or not, does the volume of distribution change? Is it high protein binding? Again, is there interactions? That's a lot to know, right? So how about know a good clinical pharmacist instead? These are my, some of my students at Auburn University. So in summary, I just wanted to impress on you how important pharmacokinetics are and how variable they are in both pediatrics, critical care, and of course, in liver failure. All areas of pharmacokinetics are affected by liver failure, and of course, the Child-Pugh score does have some of its limitations. There are alternatives to Child-Pugh scores to guide your dosing, but we really need a lot more studies before we can go another route, I feel. So instead, take a conservative approach for dosing. Utilize what known information you might have about the medications, and really think about all of your individual patient-specific factors. The rest of the slides, again, there are some of the medications that are used in the PICU that are just, they do have some specific hepatic dose adjustments, and I just wanted to list them for references. That's all I have, thank you. Thank you.

dose adjustment

liver failure

pharmacokinetics

oral absorption

distribution

metabolism