Posaconazole Tablets May Disrupt Steroid Biosynthesis, Cause Hypertension

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SAN DIEGO—Two patients developed new-onset hypertension, hypokalemia and alkalosis within a month of starting posaconazole tablets, authors reported at IDWeek 2017.

The patients’ normal deoxycorticosterone levels “confirms normal function of 11β–hydroxylase and the observed effects in our patients are thus downstream from this enzyme,” reported study coauthor George R. Thompson, MD, Internal Medicine, University of California Davis Medical Center, Sacramento, CA.

“Posaconazole induced disruption of the steroid biosynthesis pathway in patients has not previously been described, but has been suggested by in vitro studies,” Dr. Thompson said.

Earlier studies suggest that posaconazole delayed-release tablets have “superior bioavailability compared to the liquid suspension formulation,” Dr. Thompson reported. “As higher serum posaconazole concentrations have been associated with improved clinical responses, this formulation has been a welcome addition to available treatment options.” 

But higher serum and tissue posaconazole concentrations suggested undescribed toxicity, Dr. Thompson noted, citing reported off-target adverse events.  

The team therefore prospectively identified 2 patients with new onset hypertension, hypokalemia and alkalosis after starting posaconazole tablets, with normal vital and laboratory values at baseline, who developed hypertension within 30 days, with an average systolic BP increase of 59mmHg. Serum posaconazole levels were 4.3 and 4.6μg/mL.

Both patients had suppression of renin and aldosterone, with increased 11-deoxycortisol, estradiol levels and cortisol/cortisone ratios, the team reported.  

Trans-tubular potassium gradient (TTKG) was “inappropriately elevated” in each patient noted Dr. Thompson.

“Our patients’ laboratory results show clinically significant inhibition of 11β-hydroxysteroid dehydrogenase enzyme type 2 isoform (11β-HSD2) as evidenced by: the elevated 11-deoxycortisol (with subsequent suppression of renin and aldosterone), the highly elevated cortisol/cortisone ratio, and the inappropriately elevated TTKG in the setting of hypokalemia,” Dr. Thompson reported.

The findings “support in vitro predictions and highlight the clinical sequelae of posaconazole-mediated inhibition of 11β-HSD2,” he said. “Additional studies are necessary to determine the frequency of posaconazole induced apparent mineralocorticoid excess (AME) syndrome and whether other azole antifungals can be associated with this phenomenon.”

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Reference: 

Thompson GR, Chang D, Wittenberg R, Semrad A. Posaconazole induced hypertension and hypokalemia: mechanistic evaluation. Poster presented at IDWeek; October 4–8, 2017; San Diego, CA. http://www.idweek.org.