Jeffrey F. Barletta, BS, PharmD, FCCM, Professor and Vice-Chair of the Department of Pharmacy Practice at Midwestern University College of Pharmacy discussed the challenges and intricacies of weight-based dosing in the Scottsdale Institute webinar “Principles of drug dosing in patients with extreme obesity: One size does not fit all.” The presentation was sponsored by Wolters Kluwer Health.
“Obesity is not what we call a special population where there are mandates from the FDA to have dosages for this population like we see with renal insufficiency or hepatic insufficiency,” Barletta explained in the webinar. That puts the onus on pharmacists and other clinicians to be aware of weight dosage variations, calculating dosing weight, and how these factors may impact drug effectiveness and safety.
Why does weight-based dosing present so many challenges?
Obesity has been increasing in the U.S. over the past 20 years. According to self-reported adult obesity data from the Centers for Disease Control and Prevention (CDC):
- Obesity varies by region, with the highest prevalence occurring in the Midwest, Central, and Southern U.S.
- Prevalence is highest among adults aged 45-54.
- Obesity prevalence decreases with level of education.
Obesity for an adult above the age of 20 is generally defined as having a body mass index (BMI) of 30.0 kg/m2 or above. (Healthy weight BMI is 18.5-24.9 kg/m2.) Class 3 obesity, often referred to as severe obesity, are those with a BMI in excess of 40 kg/m2.
Barletta notes study data that showed the prevalence of adults with a BMI of 40 kg/m2 in 1999 was 4.7%, but it doubled to 9.2% by 2018, translating to 1 in 11 people with a BMI in excess of 40 kg/m2.
“These folks are particularly important because these patients are often not well represented in the clinical trials or the pharmacokinetic studies that are done that ultimately lead to the doses that are in product labels or package inserts,” he explains.
Drug dosing recommendations are informed largely by pharmacokinetic studies, but when it comes to patients with obesity, these studies have limitations, Barletta says:
- Most have small sample sizes (sometimes single digits) of patients with obesity.
- Few studies include patients with extreme forms of obesity (e.g., a patient of 150 kg when dosing data ends at 120 kg).
- They rarely account for pharmacogenetic variability or comorbidities.
“So not only do these patients have extreme obesity, but some may have acute kidney injury, some may have hepatic insufficiency, some may have augmented renal clearance,” Barletta says. “So, we have to factor all of these forms of variability when we craft a dose.”
Which is the ‘right way’ to calculate dosing weight?
Part of the challenge in determining appropriate weight-based dosing is how you go about calculating a patient’s weight.
Barletta notes that there are various size descriptors, in addition total body weight, that clinicians can chose to calculate weight, including:
- Lean body weight
- Ideal body weight
- Adjusted body weight
- Body mass index (BMI)
- Body surface area
“In my opinion, lean body weight is probably the best representation of fat-free mass,” Barletta says. In the webinar, he shared a formula published in Clinical Pharmacokinetics in 2005, which he notes, is the most validated for calculating lean body weight, and thus the most recommended to have at the bedside in an automated program or calculator to assist with patient assessments. He strongly cautions against doing the math by hand.
Another option, ideal body weight, is most often calculated using the Devine equation, which was first published in 1974. Barletta explains that this formula has its origins in life insurance tables from the 1950s, rather than from scientific studies in medicine or nutrition. “There was a thought that for a given height, you have a desirable or an ideal weight,” he says. “The only factors that go into this formula are sex and height. So basically, it's a linear transformation of height to a weight. Obviously, this formula is limited because it doesn't account for that increase in lean body mass that occurs when we gain weight.”
Body mass index is strictly used to characterize obesity and isn’t applicable for drug dosing. Body surface area can be taken into account for weight-based dosing calculations, Barletta says, but is used almost exclusively in the oncology world.
“All of those size descriptors are limited by the fact that they do not distinguish fat mass from fat-free mass,” he says. To illustrate his point, he demonstrated how three patients of the same height weighing 110 kg could have completely different types of body mass: one, very muscular with primarily lean body mass; one with very little lean body mass and primarily adipose tissue; and one that is carrying excess water weight due to edema. Three vastly different patients who weigh the same, but if they were to receive the same weight-based dose, the concentrations achieved would vary based on the makeup of their mass.
Physiologic changes: Why weight-based dosing matters
Obesity is associated with a number of physiologic changes that affect overall patient health, including:
- Decreased pulmonary function and increased airway resistance
- Increased liver mass
- Enzyme changes
- Increased heart weight, blood volume, and cardiac output
- Increased kidney weight and glomerular filtration rate (GFR)
- Increased subcutaneous thickness
“There really is no consistency with increasing size and organ size,” says Barletta. “So, sadly, as you gain weight, your brain does not get any bigger. But other organs, like your liver, your heart, or your kidneys, they do increase in size.”
He also notes that organ function is highly variable in patients with obesity. “With one organ system, like the lungs, we see a decrease in pulmonary function, a decrease in respiratory compliance, increased work of breathing. But other organs, like the heart, there's an increase in blood volume and an increase in cardiac output. With the liver, we see some variability in metabolism depending on the particular enzyme system. So, every organ system is affected differently.”
Not only can every system be affected differently, but the change in size and function is not directly proportional to the change in weight, he notes. If you are examining two patients, and one is twice as big as in terms of total body weight, it doesn't mean that they will have twice as much blood volume as the patient with less body mass.
What are the implications for medications?
There are two pharmacokinetic variables that best describe drug disposition in the body, Barletta explains:
- Volume of distribution
- Clearance
Volume of distribution is the hypothetical “space” in which a drug must distribute, or “fill,” in order to have a therapeutic concentration. Drugs that distribute into lean tissue typically have a small volume of distribution, whereas drugs that distribute into adipose tissue typically have a larger volume to fill, Barletta explains. This variable mostly affects single drug doses, such as a bolus dose.
“Clearance is the most important variable to consider when we're talking about a maintenance dose,” he says. “Clearance is typically affected by increases in lean tissue or metabolically active tissue, and while clearance can increase with obesity, remember, we do see a slight increase in lean tissue as we gain weight, but the extent is quite variable.” Because of this variability, estimating clearance using formulas can lead to harmful medication errors, Barletta says, particularly if the wrong weight is calculated.
Another factor to consider is the route of administration. For patients with obesity, the subcutaneous or intramuscular routes can affect the efficacy of their treatment, Barletta says. Because patients with obesity often have a greater amount of subcutaneous adipose tissue, if the needle chosen for an IM injection is not long enough to get through the tissue, the drug can be injected accidentally into the subcutaneous tissue instead of the muscle. This can interfere with absorption and has been shown to have lessened the effectiveness of vaccines in patients with obesity.
Barletta recommends pharmacists and other clinicians refer to references that include dosing recommendations for obesity to help support their decision-making, noting UpToDate® Lexidrug™ (formerly Lexicomp®) is the only drug reference that includes dosing for severe obesity as well.
To learn more, watch Dr. Barletta’s webinar, “Principles of drug dosing in patients with extreme obesity: One size does not fit all.” This webinar was first presented to the Scottsdale Institute Members.