Biologic Dosing and Obesity Save

A 46-year-old with psoriatic arthritis and a BMI of 38 still has active disease on adalimumab (Humira) 40 mg every other week. What do you do? Switch class, optimize methotrexate, or ask whether the dose itself is too low? Stephen Balevic, MD, PhD, discusses this question in "Prescribing the Right Dose: How Obesity Alters Drug Pharmacokinetics" (Monday, Nov 9), part of the "Size Matters" session.

Why standard biologic doses may fall short in obesity

A meta-analysis of 54 cohorts (19,372 patients) found people with obesity were 60% more likely to fail a TNF inhibitor, and higher failure with obesity has also been reported for tocilizumab, JAK inhibitors and methotrexate. The logic is simple: drug exposure equals dose divided by clearance, and clearance rises with body weight for adalimumab, etanercept, ustekinumab, secukinumab, golimumab and tocilizumab. In the NIH ACTIV-1 trial, where about half of patients had obesity, infliximab and abatacept exposure fell as BMI rose. Dr. Balevic estimates that matching a 70 kg patient's drug exposure takes about 40% more adalimumab at 107 kg and 43% more tocilizumab at 140 kg.

Three ways to adjust biologic prescribing in obesity

Dr. Balevic's suggestions are to choose weight-based drugs (infliximab over adalimumab, IV over SC golimumab), check drug levels, or escalate empirically, such as adalimumab weekly in patients with obesity. He rates fixed-dose adalimumab, etanercept, certolizumab, SC golimumab and SC secukinumab at highest risk of underdosing in obesity, and mg/kg agents at lowest. For the clinical vignette at the start of this article, weekly adalimumab over another fixed-dose switch or subcutaneous methotrexate is suggested based on Dr. Balevic’s suggested approach and a PsA study in which about 30% of patients with active disease improved after escalation. A weight-based IV agent is the alternative route.

His highlights that no interventional dose-escalation studies exist in obesity, that insurance and patient preference shape the decision, and that a higher dose alone does not guarantee response. A related poster (1496, Monday, Nov 9) reports that children with obesity and JIA may need higher adalimumab doses.

But does BMI tell the whole story? Not entirely. 

BMI is the usual measure of obesity, yet it can look normal in someone with low muscle mass, and that matters because both body fat and muscle shape physical function, which in turn drives disease activity and outcomes. Posters 479 (Sunday, Nov 8) and 1804 (Monday, Nov 9) examine this link in RA, relating muscle and fat phenotypes to disease activity and disability. For dosing, Dr. Balevic’s estimates are built on body weight alone, and whether lean mass also changes drug clearance remains unclear.

So if heavier patients may need more drug, should dosing be adjusted as patients lose weight with increasing use of GLP-1 receptor agonists? In TOGETHER-PsA, patients lost about 20% of body weight in a year, so the question is not abstract. And relatedly, might older adults with sarcopenia or a low BMI need less?

In summary, fixed dosing may not be best for patients with obesity. When disease stays active, consider body size as a cause of low drug exposure and adjust the dose, whether by shortening the dosing interval or switching to a weight-based IV regimen, ideally with drug levels as a guide.