Hello, welcome to our session, Obesity, A Look Behind the Curtain. My name is Jeff Barletta, and I'm professor and vice chair of pharmacy practice at Midwestern University College of Pharmacy in Glendale, Arizona. The focus of my talk is on the effect of obesity on pharmacotherapeutics. My talk is divided into two key areas. First is the principles of drug dosing in obesity, where I'll provide an overview of the problem with respect to drug dosing, the physiologic changes with obesity and implications they may have on drug pharmacokinetics, and then a brief review of size descriptors that are commonly used in the literature and in practice. The second part will focus on application of dosing principles, where I'll provide clinical scenarios and review the literature for some of the more commonly used ICU drugs. Let's start with some data from the CDC. This figure illustrates the prevalence of obesity in the U.S. over about a 20-year period. We're going to focus on the people with severe obesity, which is defined as a BMI in excess of 40, and we're going to focus here because this is the population where most of the dosing questions lie because these folks are often not well represented in the clinical trials that led to the dose listed in the product label. As of 2017, 9.2% of people in the U.S. have severe obesity. This translates to one out of 11 people having a BMI in excess of 40, severe obesity. Now if we break this down even further, specifically by sex, age, and race, you can see there are differences with obesity being more prevalent in women, middle-aged individuals, and non-Hispanic blacks. There are many challenges with dosing medications in obesity, beginning with the lack of guidance from industry in the product labels. In fact, a study evaluating 100 of the most commonly used IV drugs in the ICU reported only 30 had some reference to a weight descriptor. Now note, this doesn't mean that a recommendation was provided, but simply a reference to a weight descriptor. Second is there are very few outcome studies in patients with obesity, with most data coming from pharmacokinetic studies, and even within those pharmacokinetic studies, many had small sample sizes. It's not uncommon to find ends in the single digits. Many are not inclusive of patients with more extreme forms of obesity, which makes it difficult to craft a dose for, say, a 150-kilogram patient, when all the data available only goes up to, say, 120 kilos. Finally, in the ICU setting, we can't forget about the pharmacokinetic variability that's associated with critical illness. Now on a positive note, some tertiary references are now beginning to include obesity-specific recommendations for a few medications, which is a trend that I hope we'll see continue, but ultimately we need the data to help form and craft these recommendations. Obesity results in many physiologic changes, which are represented here, and these were nicely described in one of the other talks in this session. A few points I would like to make are that the physiologic changes vary based on organ system, where in some cases there's an increase in organ function, while in others there may be a decrease. Second is that changes in organ size is not always consistent, so sadly your brain doesn't increase in size, but other organs like your liver, your kidneys, and your heart do. Last, in all cases, the changes in organ size are not proportional to the changes in weight. What are the implications for medications? The two pharmacokinetic parameters used to describe drug disposition in the body are volume of distribution and clearance. Volume of distribution is the most important variable when dealing with a single dose of a medication, such as a loading dose. And generally speaking, drugs that distribute into lean tissue have a small volume of distribution, whereas drugs that distribute into adipose tissue have a large volume of distribution. Now unfortunately, the reverse interpretation of that isn't always true, so we can't say that all drugs with a large volume of distribution will distribute into adipose tissue, and the best example of that exception would be digoxin. Now clearance is the most important variable to consider for a maintenance dose, and clearance is typically affected by increases in lean tissue, which is metabolically active, and clearance can increase with obesity, but the extent of that increase is variable. Now usually with clearance, the increases that we see are typically not proportional to the increases in weight. Some of these pharmacokinetic implications are illustrated here. When we give a medication to a patient with normal body habitus, that medication will distribute, achieve a certain concentration at an effect site, and hopefully those concentrations will reach the pharmacodynamic goal that has been established for that medication, and the final outcome is treatment success. With obesity, however, there is significant pharmacokinetic variability that can adversely affect this process. For example, the scenario in the middle represents inappropriately using ideal body weight for a medication that is largely impacted by obesity. Subtherapeutic concentrations are achieved, we fall short of our pharmacodynamic goal, and the outcome is treatment failure. The scenario shown on the bottom represents inappropriately using total body weight for a medication that is not impacted by obesity. Supertherapeutic concentrations are achieved, and the end result here is an adverse drug event. When we evaluate the pharmacokinetic properties of a drug and the potential impact obesity may have, what we're really looking for is dose proportionality. And dose proportionality is, as total body weight increases, volume of distribution and clearance will increase by that same ratio. So to illustrate this, there are two examples shown in this table, drug A and drug B, and the volume of distribution and clearance for a 75-kilo patient and a 150-kilo patient. So beginning with drug A, you can see that there is a twofold difference in weight, and then a twofold difference in both volume of distribution and clearance. So this concept of dose proportionality applies. For drug B, however, you see there is not a twofold difference in volume of distribution or clearance, so dose proportionality does not apply. Another factor to pay attention to is administration technique, particularly with SubQ or IM routes. This figure illustrates the implication for needle size based on body habitus, which is especially important for IM administration. If we compare and contrast these two images, there is no difference in skin thickness, no difference in muscle, but there is a significant difference in the thickness of the SubQ layer. So you can see in this image on the right that the needle is not long enough to reach the muscle, resulting in inadvertent injection into SubQ tissue. Now the clinical implications of this are that absorption from SubQ tissue is slow and gradual. In fact, if you look at studies with vaccines, they've actually shown a lower antibody response with SubQ administration compared to IM. Now with SubQ injection, when that is the intent, needle size is less relevant, but because there is more subcutaneous tissue, absorption can be delayed and bioavailability reduced. Before I talk about specific medications and dosing, it's important to describe the various size descriptors that are referred to both in practice and in the literature. The first one is lean body weight, and lean body weight provides one of the better representations of fat-free mass because these formulas do account for the increase in lean mass that occurs with an increase in fat mass. Now there are many different formulas for lean body weight that you'll see in the literature and when you do a search, so it's important that you choose the one that's most accurate and that's been most validated, which is the one that I have listed here, which is referenced at the bottom of the slide. The next weight metric listed is ideal body weight, and most people are familiar with this formula. There are, however, many limitations with ideal body weight, and as you can see, that it's solely calculated based on sex and height. Now some people refer to ideal body weight as a surrogate for lean body weight, which is really inaccurate because it does not account for the increase in lean body mass that occurs as size increases. A better surrogate, if you are going to use one, is adjusted body weight, and the formula for adjusted body weight is listed here. It's ideal body weight plus a correction factor times the difference between total and ideal weight. Now the correction factor that's most commonly used in practice is 0.4, but there is significant variability that you'll see in the literature with a wide range of correction factors, but 0.4 is the one that's most commonly used. Body mass index is used to characterize obesity, but we really don't use BMI for weight-based dosing in practice. And then finally, body surface area. Body surface area really isn't used all that much in the ICU, but it is used quite widely in the oncology world. Now all of these size descriptors are limited by their inability to distinguish fat mass from fat-free mass. So let's take this example. We have three patients, all of the same height, age, and weight. Patient one, you can see, has increased muscle mass or increased lean body mass. Patient two has increased fat mass, and patient three has increased water weight due to edema. Now although all three of these patients weigh the same, there are substantial differences in the makeup of that weight, which will heavily influence and impact drug disposition. All right, so the second part of my talk will focus on application of these dosing principles and a review of some specific drug recommendations. Now obviously I can't talk about every drug that's used in the ICU, but I picked the ones where maybe there are more questions or even some misconceptions. So let's start with sedation. You're starting propofol for sedation in a patient who weighs 160 kilograms and the BMI is 47. You open up your order entry screen, and maybe it looks something like this, where you have to select a sedation goal. So we choose light sedation. The dose is listed here. We have to pick a weight, and then the admin instructions are listed below. So my question for you to consider is, in your practice, which weight is used most frequently? Recorded body weight, which is the total body weight today, ideal body weight, adjusted body weight, or admit body weight, which is total body weight on admission. So as we know, propofol is one of the recommended agents for sedation according to the SCCM PATAS guidelines. If you look at the pharmacokinetics of propofol, it has a large volume of distribution and is highly lipophilic. So if you look solely at these values, you might think that total body weight would be the most appropriate weight metric to use for dosing. However, when you look at the pharmacokinetic data, and I'll tell you that all of the data with propofol in obesity originate from the OR theater. So you can really question the generalizability here, but you'll find that the relationship between clearance and total body weight is nonlinear. So this would mean that using total body weight is not appropriate and could lead to excessive doses. So dosing using either ideal body weight or adjusted body weight would be preferred. Now whenever I talk about propofol in obesity and emphasize the importance of choosing the right weight metric, people always ask me, well, why does it matter since you're going to titrate it to effect anyways? Well, let me show you. Here you see what many consider to be a starting dose and a max dose calculated using ideal body weight, adjusted body weight, and actual body weight for a 70 kilo, 100 kilo, and 140 kilogram patient. So let's focus on this column for the 140 kilo patient, and you can see the tremendous differences in dose based on the weight metric that's used. Now we know that propofol is associated with adverse cardiovascular effects, so by choosing the wrong weight, there is potentially an increased risk for cardiovascular adverse drug events like hypotension. Now let's look at the max weight of 80 mikes per kilo per minute, and again, you see tremendous differences in the calculated dose based on the weight metric that's used. Now I've taken this dose calculated according to actual body weight and then reconverted this dose to a weight based dose, mikes per kilo per minute, using either ideal body weight or adjusted body weight, and you can see the calculated doses, and these are quite alarming and far beyond what I think most of us would be comfortable with. Well, how about anticoagulation and VTE prophylaxis? My question for you is, what dose of inoxaparin do you most commonly use in a 160 kilo patient with a BMI of 47 with normal renal function? And your choices are 40 milligrams once a day, 30 milligrams twice a day, 40 milligrams twice daily, 0.5 mikes per kilo twice daily, or perhaps some other dose. When we look at the data with inoxaparin, you'll find that most of the data in obesity is based on anti-10A levels. So there are really few data out there that use VTE rate as the primary outcome. This is one of those studies, and this was conducted in the bariatric surgery population. This was a pre-post study evaluating the impact of a protocol using 40 milligrams twice a day versus a historical approach of 30 milligrams BID, and as you can see, there was a significant reduction in VTE rate using the higher dose of 40 milligrams twice a day. This is the second study that reported a reduction in VTE rate as the primary outcome, and it was conducted in just general hospitalized patients. And here the results were stratified according to BMI, so we'll want to focus on the cohort with a BMI in excess of 40, and then standard and high doses were compared with high doses being defined as inoxaparin, 40 milligrams twice a day, or heparin, 7,500 units, TID. So this study included both low molecular weight heparin and unfractionated heparin. However, most of the patients included here received low molecular weight heparin. And as you can see, that high dose prophylaxis was associated with a lower VTE rate. Others have suggested that even higher doses may be necessary, particularly in those patients with more extreme forms of obesity. And theoretically, this makes sense because if we're saying that higher doses are needed in patients with a BMI of 40 compared to, say, a BMI of 25, then you likely need a higher dose in patients with BMIs in the 50 or 60 range compared to those with a BMI of 40. So this paper evaluated a BMI-adjusted strategy where patients with a BMI in excess of 50 received 60 milligrams of inoxaparin every 12 hours compared to a standard dose of 40 milligrams every 12 hours. And the results are shown here, and what you want to focus on are the percentage of patients with subtherapeutic concentrations, and you can see these are relatively similar. And this indicates that, yes, we did need a higher dose in order to achieve a similar rate of therapeutic concentrations. Another strategy that has been described is weight-based dosing. Several studies have evaluated this approach, which are highlighted on this slide. Now, there's a couple of things I want to point out. Versus if you look at the BMI of these studies, you can see that it ranges anywhere between 35 and 61. The population of patients included is somewhat variable, medically ill, non-ICU patients, surgical ICU patients, trauma patients, and then finally the dose. The dose consists of either 0.5 milligrams per kilogram once a day or 0.5 milligrams per kilogram twice a day. Now what's interesting is that when we look at the results, the success rates in each of these studies were all the same despite the fact that different doses were utilized, 0.5 per kilo once a day versus twice a day. Now I really don't have a good explanation as to why this may have occurred other than perhaps maybe the differences in BMI of the patients included or perhaps the heterogeneity in the study populations with some patients being critically ill while in other studies they included primarily non-ICU patients. Let's move on to infectious disease. Vancomycin is a drug where there's a lot of questions and a lot of challenges. This study reported the pharmacokinetic alterations that exist with vancomycin obesity. If we go back to that concept of dose proportionality, you can see with volume of distribution that dose proportionality does not exist, however for clearance it does. So this would indicate that total body weight would be most appropriate for maintenance doses, but I'll tell you that vancomycin is an exception to that rule because when we look at a real-world cohort, the results are somewhat different. So this is a study that evaluated obese patients. The mean weight was 139 kilos, BMI of about 46, and what you see in this figure are the results stratified by the doses that led to a therapeutic trough concentration, and the therapeutic trough concentration was defined as between 15 and 20. So you can see that the doses here ranged anywhere between 1 gram and 3 grams. Now if total body weight were the most appropriate weight metric to use here, you would expect to see much higher daily doses being required in order to hit these target troughs. If we look at their conclusion, it reads, in extremely obese patients, the dose category of 20 to 25 milligrams per kilogram per day based on total body weight was associated with the higher odds of target trough attainment. So about 25 mg per kilo per day, which is much lower than what we would typically dose these patients on provided they have normal renal function. But I want you to remember that number, 25 mg per kilo per day. A second study developed an AUC-based nomogram, and this process begins by calculating clearance using the formula that's listed here on the bottom of the slide. After you have your clearance, you simply look at the respective loading and maintenance dose that's required. Now to give you an idea where most people would fall on this nomogram, I've created four hypothetical patients, all weighing 160 kilos, but with different ages and different degrees of renal function. Now let's focus on, say, a middle-aged individual with normal renal function. And you can see that the calculated clearance here is about 7 to 8. While with this degree of clearance, the average dose is 25 mg per kilogram per day. So consistent with the conclusion of the previous study, and I'll tell you that this is one of the first time at least that I've seen some consistency in the data regarding vancomycin dosing in obesity. Studies for vancomycin dosing were published in 2020, and they recommend a loading dose of 20 to 25 mg per kilo using total body weight, with a maximum dose of 3 grams. Maintenance doses for most obesity patients usually do not exceed 4.5 grams per day, and early and frequent monitoring of AUC exposure should be performed. Vancomycin is an interesting drug because the package insert recommends dosing using total body weight. But if you look at the origin of that recommendation, it comes from a small pharmacokinetic study where clearance was higher in obese patients. Now while that may be true, it does not necessarily mean that dose proportionality applies, and this is nicely illustrated in this paper. So here you see two groups, the obese and non-obese cohorts, and you can see that the weight in the BMI, the differences here, are about a two-fold difference between these two groups. But now when you look at volume of distribution and clearance, you see there is not a two-fold increase in these values, which would indicate that dose proportionality does not apply. As a result, higher C-max and higher AUCs are observed in the obese cohort. So perhaps with daptomycin, total body weight is not the most appropriate weight metric to use, and something like adjusted body weight or lean body weight would be a better option. The last drug I'd like to talk about is priprocillin and tezobactam. And the point I'd really like to emphasize here is the value of using either prolonged or extended infusions over short intermittent infusions of either 30 or 60 minutes. And what you see here on this slide is the probability of target attainment for different MICs. And again, you can see with short intermittent infusions, we tend to fall short of reaching that target with much better success rates using the extended or prolonged infusion. So in my practice, the dose that I most often use in patients with obesity, provided they have good renal function, is 4.5 grams every six hours as an extended infusion. All right, so in conclusion, high-quality evidence is limited to guide medication dosing in critically ill patients with extreme obesity. An individualized dosing approach is necessary, and the role of therapeutic drug monitoring should be expanded. Thank you for your time and willingness to listen to this presentation.

Obesity

medications

dosing

pharmacokinetic data

weight metric

specific medications