New Evidence on Posaconazole Safety in Persons with Obesity

A new physiologically based pharmacokinetic (PBPK) study demonstrates that the elimination half-life of posaconazole is significantly prolonged in individuals with obesity – especially those with a BMI ≥ 35 kg/m² – compared to people with normal weight. The labeled half-life for posaconazole is typically 26–35 hours. But in persons with obesity, this can extend to nearly 58 hours – almost twice as long.

In other words, this drug hangs around longer in the body of a person with obesity.

Why It Matters

This matters clinically for a simple reason: posaconazole is a potent and irreversible inhibitor of the CYP3A4 enzyme, which metabolizes many widely used medications. A longer half-life means prolonged inhibition – which can persist for days after the drug is stopped, increasing the risk of drug-drug interactions that can lead to toxicity or treatment failure. Studies using sensitive CYP3A4 substrates like ranolazine and lurasidone confirmed that this risk is amplified in people with obesity.

By now, the evidence for this problem and its mechanism is substantial. Posaconazole distributes more broadly into fat tissue, which increases its volume of distribution without a proportional increase in clearance. This is not a theoretical concern. It’s observable, reproducible, and now documented in modeling and clinical studies.

And yet – despite this clear evidence – the current FDA and EMA drug labeling for posaconazole makes no mention of this prolonged half-life in persons with obesity. There is no guidance for adjusting wash-out periods or anticipating persistent interactions in patients with higher BMI.

What Clinicians Need to Do Now

• Assume a longer half-life and longer pharmacologic effects in patients with obesity.
• Be especially cautious with CYP3A4 substrates following posaconazole use.
• Extend wash-out periods beyond standard 3–5 half-lives if based on normal-weight assumptions.
• Monitor for delayed interactions, particularly with narrow-therapeutic-index drugs.

What Regulators and Manufacturers Must Do

So this omission in drug labeling is not just a gap in information – it is a mistake. One that places patients at risk. Documentation of altered posaconazole pharmacokinetics in obesity is now clear. Prescribers deserve clear guidance. Patients deserve safe care.

FDA and the manufacturer (Merck) should update posaconazole labeling immediately to reflect the longer half-life in persons with obesity and to equip clinicians for managing that risk. Anything less ignores the realities of obesity pharmacology – and undermines the safe use of this important antifungal therapy. Worse, it discounts the safety of persons with obesity who need this drug.

Click here for the new study in the Journal of Pharmacokinetics and Pharmacodynamics. For further perspective, click here, here, and here.

Proceed with Caution, photograph by Edna Winti, licensed under CC BY 2.0

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August 1, 2025