Overdue EMA reflection paper on drug dosing in obesity introduces more questions than answers

Background: The prevalence of obesity, and its complications, in Europe

• Obesity is generally defined using a crude metric referred to as body mass index (BMI). BMI is calculated using only height and weight, and does not factor in biological sex, muscle mass, age, or various other factors that can have major effects on total weight and total body fat. There is currently a strong push in the medical field to move beyond the use of BMI to define obesity and instead utilize measures like waist-to-hip ratio, which are more likely to predict body fat percentage and thus more likely to predict long-term health risks. Regardless, weight class for adults is currently defined by the World Health Organization (WHO) using the following BMIs, expressed as kg/m^2: 1) Normal weight: 18.5-24.9, 2) Overweight: 25-29.9, 3) Class I Obesity: 30-34.9, 4) Class II Obesity: 35-39.9, 5) Class III Obesity: 40+.
• Since 2019, more than half of the population of Europe has been classified as overweight or obese. According to Eurostat, the prevalence of overweight and obesity in adults in 2019 (the most recent year with complete data) was 53%. This rate varied significantly between countries and by biological sex. For females, the lowest rate of overweight and obesity occurred in Italy, at 37%; the highest rate occurred in Croatia at 59%. For males, the rate ranged from 53% to 73%, with those rates occurring in France and Croatia, respectively. The figures are lower for individuals meeting obesity criteria, with 2019 data showing just 16.3% of Europeans meeting that mark.
• Many factors contribute to the development of obesity; the influence of a host of risk factors varies widely by individual. Some of the most well-recognized contributors to obesity include eating habits and physical activity patterns. Other lifestyle factors, such as inadequate sleep as a child or adult, have also been shown to contribute to weight gain. It’s important to recognize that many of these factors are influenced by social determinants of health (SDOH), or the “conditions in which we live, learn, work, and play.” If these conditions do not provide access to affordable, healthy foods or safe places to exercise, then they can contribute to weight gain. The genetic contribution to obesity is still being explored, but twin studies indicate high heritability, with multiple genetic variants likely contributing by means such as increasing hunger and food intake. Environmental exposures may also play a role, such as exposure to endocrine disruptors.
• Obesity itself contributes to multiple long-term consequences, including high blood pressure and high cholesterol, which in turn increase the risk of heart disease. For example, a survey conducted in Europe in 2022 determined that by self-report, 39% of adults with obesity also had hypertension, 26% had type 2 diabetes, and 21% had osteoarthritis. Perhaps most importantly, 75% of participants reportedd at least one obesity-related complication; 26% of participants had three or more such complications. Other complications of obesity include increased fat content in the liver, which can lead to liver dysfunction, and increased risk for breathing problems such as sleep apnea. Adults with obesity also have a higher risk of many types of cancer and certain types of mental illness, such as depression and anxiety.

Background: Body composition and drugs

• The actual passage of a drug through the body is a strong determinant of its therapeutic and toxic effects. That passage is referred to as pharmacokinetics (PK) and incorporates four important phases – absorption, distribution, metabolism, and excretion (ADME). Individual differences in weight, age, biological sex, fat and water content, organ function, and more can alter the PK of a drug and, in turn, alter the effects of the drug, potentially increasing or decreasing its effects and toxicity.
• Absorption refers to the amount of the drug that is taken from the place of administration to the site of action. Although most people may think of this phase in relation to absorbing an oral drug from the gut, absorption technically occurs through all routes of administration. As may be expected, drugs that are injected into the body tend to have a higher absorption rate than drugs that are taken by mouth. In patients with higher body fat content, drugs administered through the skin or via injection into the fat tissue (subcutaneous) or muscle (intramuscular) may be absorbed differently than in patients with lower body fat or higher muscle mass.
• Distribution acknowledges the extent to which the drug disperses throughout the body, including to various organs, compartments and sites of activity. Depending on the properties of a given drug, body fat and body water content can have a dramatic impact on its distribution. If a drug is highly hydrophilic (water-loving), and a patient has a large amount of water in the body, the drug will accumulate in the water, reducing the amount of drug that reaches the target site. This is a common concern in people with heart failure who have fluid retention, as well as people with liver failure who develop ascites. In people with a large content of fat – also referred to as adipose tissue – a drug that is lipophilic (fat-loving) can accumulate in the fat tissue, reducing the amount of drug available to reach the target site. These are only two of many ways that a drug’s distribution may be altered by body composition.
• Metabolism is the process by which a drug is modified in the body. In many cases, this involves breaking the drug down into multiple metabolites that can then be eliminated by the body. But for some drugs, metabolism activates the drug, creating active metabolites that provide the intended effects. Thus, changes in metabolism can both increase and decrease the effects of a drug, depending on the drug itself. The field of pharmacogenomics has shown that genetics can play an important role in drug metabolism. But people with higher body mass may also have altered drug metabolism, with research suggesting that metabolizing enzymes may have increased, decreased, or no change in activity in people with obesity, depending on the enzyme.
• Finally, a drug is excreted, or eliminated, from the body through a variety of pathways. Drug elimination most commonly occurs through the liver and kidneys. The actual pathway for elimination is an important consideration for any drug, as is the rate of elimination from the body. Some drugs may clear the body entirely within eight hours, whereas others may stay around for months. Unsurprisingly, changes in drug distribution can have an effect on the rate of elimination. For example, if a drug has accumulated in adipose tissue, it may remain in the body for a much longer duration as it slowly releases from the fat tissue into the rest of the body. Conversely, in people with higher body fat percentage, drugs that are eliminated through the kidneys seem to be eliminated faster. This is thought to be due to changes in regional blood flow, cardiac output and complex feedback mechanisms that can change in response to increased weight and/or body fat percentage.
• Considering all phases of ADME together, some drugs will be more affected by body fat percentage than others. Drugs with high lipophilicity would be anticipated to have a more pronounced shift in PK when administered to patients with a higher or lower body fat percentage. Drugs intended to be given via certain routes of administration will also have an increased risk for alterations, and the same drug may be affected differently by body fat percentage depending on its route of administration (IV or oral, for example). Drugs that are metabolized by the liver and/or excreted by the kidneys can be affected by body fat percentage as well.
• But body fat percentage matters in people without obesity, too, and body fat is not the only relevant factor to a drug’s PK. Humans experience natural changes in body composition over the life span. Every human begins life with a relatively high water content, rapidly transitioning to a more stable body composition in early childhood. At this point, lifestyle begins to impact body composition through alterations in fat and muscle mass. As humans enter older adulthood, another shift occurs – a relative loss of muscle leading to an increase in body fat percentage. This particular shift is more dramatic in postmenopausal females who experience a more profound shift in body composition. Thus, lifelong alterations in water, fat and muscle content affect drug PK.
• And what about the effect of weight as a whole? Body weight is a classic consideration for drug dosing. This is apparent for drugs that are actually dosed by weight. It is less apparent for drugs that have a recommended dosing range that is not specifically guided by body weight. However, it is not unusual for patients with a higher body mass to require higher doses of a given drug to achieve the desired effect when compared to patients with a lower body mass. That being said, body weight is a relatively blunt instrument, as it does not consider any of a drug’s inherent properties that can alter PK and ADME as described above. Two patients with the same total body mass can have drastically different body compositions across water, fat and muscle.
• What little has been learned about the effects of obesity on drug disposition reveals how little is truly known. For examples and further discussions of existing knowledge on this topic, see AgencyIQ’s deep dive on obesity and drug dosing.

To date, regulators have offered little in the way of guidance to sponsors developing drugs for patients with obesity

• Currently, the U.S. FDA does not require that clinical trials enroll patients with varied body compositions, nor does it have a guidance document specifically addressing evaluation of drugs in people with obesity. Instead, obesity is inconsistently and often indirectly mentioned in a handful of guidance documents.
• Similarly, the EMA has not historically offered guidance on the inclusion of patients with obesity in clinical trials, or the targeted evaluation of drug disposition in these patients. In fact, one of the only guidelines from the agency that discusses obesity in any real detail is the guideline for the clinical evaluation of medicinal products used in weight control. Even the EMA’s guideline on the development of drugs for the treatment and prevention of diabetes – which was updated in 2023 – does not directly address the topic of enrolling patients with obesity or evaluating the effects of weight on drug disposition, safety or efficacy.
• Last week, the EMA published a finalized reflection paper on the topic of investigating PK in people with obesity, a project that has been in the works since 2018. Early that year, the agency published a draft reflection paper, which remained open for comments for six months. At the time, the draft reflection paper was intended to address both PK and pharmacodynamics (PD), though the final version’s title indicates a more targeted scope of PK only. Now, six years later, the agency has released the final document, with only minimal changes save the narrowed focus.

So what is the EMA’s current stance on this topic?

• Considering that the final document is a reflection paper, as opposed to a guideline, it may not be a surprise that the EMA’s recommendations remain relatively limited. In fact, the 10-page document (excluding front matter and the table of contents) devotes only the first three pages to general information regarding the effects of obesity on ADME. The last third of the document is dedicated to references, leaving just three and a half pages in total for EMA’s current thinking regarding the evaluation of obesity during drug development.
• While the title of the paper indicates a focus on PK, it does offer up one paragraph on obesity and PD, expanded when compared to the draft version of the paper. This small segment of the document – Pharmacology considerations – acknowledges the potential for obesity to alter various bodily functions, such as receptor sensitivity, platelet reactivity and macrophage activity. These wide-ranging effects have the potential to interfere with drug effects and should be kept in mind, although the paper’s authors acknowledge that “overall currently available data regarding the impact of obesity on PK/PD is limited.”
• The reflection paper also briefly addresses the effect of bariatric surgery on drug bioavailability. This paragraph, which is approximately twice the length of the paragraph in the draft document, notes that bariatric surgery – with gastric bypass and gastric sleeves being the most common procedures – can cause significant changes to the absorption and metabolism of certain drugs. The paper cites research indicating that these procedures can alter gastric emptying time, increase gastric pH and affect the ionization of drugs. Additionally, when patients experience weight loss after the surgery, the volume of lipophilic distribution would be expected to change. Thus, sponsors should be aware of the potential for a significant intra-person change in drug PK before and after bariatric surgery.
• When should a sponsor investigate the effects of obesity? The EMA provides a list of six criteria, with the presence of any one triggering an investigation: 1) When obese patients constitute a larger portion of the target population than in the general population; 2) Subcutaneous/dermal routes of administration; 3) Drug properties and/or literature indicate a potential impact of obesity on PK; 4) Body weight is expected to alter PK based on simulation; 5) Weight-based dosing is anticipated; 6) The drug has a narrow therapeutic range. While the second criterion – drugs with subcutaneous/dermal routes of administration – is new to the list, the other five criteria mirror those listed in the draft paper.
• And how should a sponsor investigate the effects of obesity? According to the EMA, sponsors should conduct a population PK (PopPK) analysis, a dedicated PK study (i.e., non-compartmental analysis) or use modelling approaches. The first two options have been carried forward from the draft paper with relatively few changes. The section on modelling approaches, however, has been expanded to include not only physiologically based PK (PBPK) models but now also quantitative systems pharmacology (QSP). Here, the agency notes that these approaches may be particularly useful when developing pediatric products.
• Finally, the reflection paper briefly reviews the presentation and discussion of such data. The EMA states that sponsors should identify target criteria, specifying the changes in exposure that would “justify a posology adjustment based on the main concern (adverse events or lack of efficacy) for the specific medicinal product.” The agency also notes that “As background for the decision on adequate treatment recommendations, simulations of the predicted exposure during treatment should be provided and should include a graphical description of concentration over time and the predicted variability in the population.” Any proposed dosing strategy should carefully consider this information, as well as the risks of under- or over-dosing and the risk of dosing errors. Overall, this section has undergone very few changes as compared to the draft version.

Analysis

• Regulatory guidance on evaluating the effects of obesity on drug disposition is greatly needed; however, this EMA reflection paper is not likely to fill that gap. The paper is relatively light on actual guidance and recommendations, instead focusing on discussions of the relevance and importance of the topic and indicating that investigations in this area should be considered when appropriate and possible. Additionally, the first criterion listed in the paper – investigating the effects of obesity when the target population has a higher rate of obesity than the general population – introduces a larger question. If more than half of the general population of Europe is already considered overweight with nearly one in five meeting obesity criteria, why is it not yet considered necessary for obesity to be evaluated in all drug development programs?
• As AgencyIQ has previously discussed, until (or if) regulatory agencies enforce stronger recommendations related to the evaluation of drugs in people with obesity, the onus falls to sponsors. There are a number of reasons for sponsors to consider proactively incorporating these patients into their clinical trials, not least of which is the expansion of the potential enrollment pool. Enrollment of these patients would also allow for a more representative trial population. Similarly, considering the likelihood of use of any approved drug by patients with obesity, it would behoove sponsors to gain a clear understanding for any differing effects – whether related to safety or efficacy – that may be expected to occur in this population prior to approval. This could both improve outcomes with real-world use and limit risks associated with toxicity and adverse effects.
• Any research conducted in patients with obesity will likely pay dividends moving forward. Further exploration through modelling or other approaches will help developers fine-tune their knowledge about the effects of body composition on where a drug goes and what it does; these efforts will expand a body of knowledge that may also eventually reduce the time and expense needed in preclinical development. As noted in some recent publications authored by FDA scientists, the FDA is supportive of the use of modelling to assist with drug development in this patient population. The development of robust models and simulations could yield opportunities to accelerate the drug development process while potentially also yielding broader dosing guidance and recommendations at the time of approval.
• What’s next? This reflection paper is finalized in its current form and is not open for consultation. Although the EMA sometimes follows a reflection paper with a guideline, the agency has not indicated any intention to do so on this particular topic. However, as this topic continues to receive attention, sponsors should keep an eye out for additional guidance from regulatory agencies in the coming years.

To contact the author of this item, please email Chelsey McIntyre ( [email protected]).
To contact the editor of this item, please email Kari Oakes ( [email protected]).

Key Documents and Dates

• Reflection paper on investigation of pharmacokinetics in the obese population