Hypokalemia and Hypertension Associated with Supratherapeutic Posaconazole Levels

LETTER

We report a case of posaconazole toxicity in a 44-year-old man with a history of diffuse large B cell lymphoma. He achieved disease remission following 4 cycles of chemotherapy, with the last cycle administered over a year prior to presentation. He presented with several weeks of fatigue, nonproductive cough, fever, and night sweats. ¹⁸F-fluoro-deoxyglucose (FDG) positron emission computed tomography demonstrated numerous FDG-avid pulmonary nodules and mediastinal and bilateral hilar adenopathy without evidence of recurrent lymphoma at the site of prior nasal involvement. Granulomatous inflammation was present upon mediastinal lymph node biopsy. Histoplasma antibody complement fixation and histoplasma urine antigen levels were consistent with pulmonary histoplasmosis. The patient was initially started on itraconazole. However, he developed generalized pruritus and an urticarial rash 5 days after starting itraconazole. The rash resolved after itraconazole was stopped. Skin testing was negative for posaconazole, fluconazole, and voriconazole. Therefore, the patient was switched to posaconazole delayed-release tablets (300 mg daily), which he tolerated without issues. A serum posaconazole level measured 2 weeks after initiation of therapy was 7,980 ng/ml; therefore, the posaconazole dose was decreased to 200 mg daily. Two months after initiating antifungal therapy, he developed fatigue, polyuria, and hypertension, with a blood pressure of 154/98 mm Hg. Serum chemistries were notable for potassium at 2.2 mmol/liter and a posaconazole level of 5,180 ng/ml. Laboratory studies were notable for mild metabolic alkalosis and a urine transtubular potassium excretion gradient of 6.3%, suggestive of inappropriate renal potassium wasting. In addition, early-morning plasma renin (<0.7 ng/ml) and aldosterone (<4.0 ng/dl) levels were undetectable, with a normal early-morning serum cortisol level (17 μg/dl). No gastrointestinal or other source of potassium loss could be identified, and the patient was on no other medications. An echocardiogram (ECG) demonstrated sinus bradycardia and a prominent U wave, prompting admission for cardiac monitoring and intravenous potassium repletion. He received 290 meq of potassium and was started on oral potassium supplementation. The posaconazole dose was further decreased to 100 mg daily. A subsequent posaconazole level was measured at 2,160 ng/ml, with resolution of the alkalosis, hypokalemia, and hypertension.

Posaconazole is a potent, extended-spectrum triazole antifungal approved for the treatment and prophylaxis of serious fungal infections. Use of the oral-suspension formulation of posaconazole is often hindered by subtherapeutic levels due to poor absorption, and high drug levels are rarely achieved. However, with the newer delayed-release tablet formulation, more patients achieve high serum drug concentrations (1, 2). At our institution, we usually obtain posaconazole trough levels at least once after initiation, with a general goal of at least 1,000 to 1,250 ng/ml for treatment of fungal infections, based on improved response rates with higher serum drug levels in a study of salvage therapy for invasive aspergillosis. Dose adjustment is not typically required with the delayed-release tablet formulation (3). In clinical trials, hypokalemia was reported in 22% of patients who received posaconazole at 300 mg daily (4). While the precise mechanism of posaconazole-induced hypokalemia is not known, the combination of hypertension, hypokalemia, undetectable plasma renin and aldosterone levels, and a normal serum cortisol level in our patient indicate apparent mineralocorticoid excess. Similar syndromes of hypertension and hypokalemia have been reported with the structurally related azoles itraconazole and ketoconazole. Whether these azoles have a direct mineralocorticoid effect or alter mineralocorticoid enzymatic pathways remains to be determined. There has been one previous similar reported case of hypokalemia and metabolic alkalosis with a high serum posaconazole level raising concern for an association between high drug levels and observed toxicity (5).