Obesity

Sonya Collins

More than 42% of Americans have obesity. Given that obesity raises risk for numerous chronic illnesses and cancers, this subset of the population likely receives a substantial proportion of the medications prescribed in the United States. But they might not be getting the right dose.

A review published online on November 18, 2023, in Current Obesity Reports highlights the dearth of understanding on how drugs work in people with obesity and the glaring need to include this population in drug approval studies.

“People with obesity aren’t routinely studied when it comes to the clinical trials that lead to drug approval,” said Christina Chow, PhD, head of research at Emerald Lake Safety and coauthor on the review. “In some cases, people with obesity may need a larger dose. In other cases, it can affect how long drugs stay around in your body. There is a lot that is just not known.”

Scope of the problem

The drugs that may work differently in people with obesity span classes and conditions. It’s not a question of simply prescribing a large enough dose for people with obesity. Though sometimes that’s the appropriate approach, it can lead to overdose in others.

Some drugs may stay in the system longer than expected, and some may not work in people of a certain weight at all regardless of the dose.

The review by Chow and colleagues highlights only a small segment of drugs that may require special considerations in patients with obesity.

For example, it takes longer for the antipsychotic drug brexpiprazole, which is indicated for schizophrenia, to reach the 90% effective concentration level in people who have obesity, which includes an estimated 58% of people with schizophrenia. Vortioxetine and diazepam both have extended half-lives in people with obesity.

As another example, the half-life of antifungal posaconazole is longer in this patient population, many of whom may be getting treatment for infections secondary to an immunosuppressive cancer therapy.

“When you stop taking a strong CYP3A inhibitor, which is what this antifungal is, you may need to wait three to five half-lives of the inhibitor before you go back on the full dose of the [cancer] medication again,” Chow said.
 “But people with obesity may need to wait up to a week longer to avoid possible drug–drug interactions, which can be dangerous.”

Tacrolimus, administered to prevent transplant rejection, may pose a risk of overdose in individuals with obesity. Dosing instructions are based on total body weight, Chow said, “so people with obesity will be given more, and studies have shown that’s actually too much. They are being overdosed.”

In people with obesity who take levonorgestrel (Plan B), the risk of pregnancy is four times greater than it is in other patients capable of pregnancy, studies show. But, Chow said, “There’s nothing on the package inserts that says, ‘This drug may not work as well in women with obesity.’ ”

Vitamin D and ibuprofen also make the list of drugs that behave differently in a patient who has obesity.

Not a one-size-fits-all solution

Because of the variety of unexpected ways that drugs may act in people over a certain BMI, there’s not a single solution to the problem. A prescriber cannot simply refer to a table that shows dose conversions based on a person’s weight. Health care providers need guidelines on each individual drug whose pharmacodynamics or pharmacokinetics is affected by obesity.

FDA does not require drugmakers to include people with obesity in clinical trials to get drug approval. In fact, members of this population may often be excluded from trials due to comorbidities.

An ideal solution might be regulations and initiatives to ensure that clinical trial cohorts better represent the population. This call has been made in discussions around race- and gender-based health disparities as well. But it may be simpler than that. Chow cited examples of drugmakers who conduct small studies during the development or approval process on patients with renal impairment to understand the drug’s effects on them.

“There are ways to start asking these questions in the approval process even without that broader inclusion,” she said. ■