Serum intraconazole and hydroxyitraconazole concentrations and interaction with digoxin in a case of chronic hypertrophic pachymenigitis caused by Aspergillus flavus

Abstract

A patient treated with itraconazole (ITCZ) under the diagnosis of Aspergillus flavus-induced chronic hypertrophic pachymeningitis is presented. The reason for the successful cure of this patient was investigated by the pharmacokinetic analysis of serum levels of ITCZ. Concurrently administered digoxin was also investigated for its drug-drug interaction. The patient (a 75-year-old male) developed ophthalmopathy, and was diagnosed as having A. flavus hypertrophic pachymeningitis by pachymeninx biopsy. After admission, he was treated with FLCZ, AMPH, 5-FC and MCZ. The infection tended to subside with the AMPH administration. Since renal insufficiency was induced by AMPH and the other antifungal drugs were ineffective, daily administration of 200 mg of ITCZ was initiated, and the inflammatory signs and symptoms gradually subsided. The symptoms did not recur during the 36 months of intraconazole treatment after discharge, and it was concluded that ITCZ was effective for A. flavus hypertrophic pachymeningitis. Pharmacokinetic parameters of ITCZ and OH-ITCZ as follows: ITCZ: C(max) 93.2 ng/ml, T(1/2β) 11 hours, AUC0-24 999 ng · h/ml, OH- ITCZ: C(max) 159.4 ng/ml, T(1/2β) 16.2 hours, AUC0-24 of 1391 ng · h/ml. Both ITCZ and OH-ITCZ reached steady states seven days after administration began. The ITCZ and OH-ITCZ levels in serum collected 36 months after the initiation of administration were 452.9 ng/ml and 1233.6 ng/ml, respectively. C(max) and AUC0-24 of ITCZ and OH-ITCZ on the second day were markedly lower than those in healthy adults reported by Oguchi et al., and hypoalbuminemia observed at administration on that day was considered the most probable cause. It was assumed that the most plausible reason for a successful cure even at a low dose of ITCZ was the increase of distribution to tissue by the increase of the unbound form. Digoxin was concurrently given to this patient at 0.125 mg/day, but the blood digoxin level was not elevated. Consideration of the blood level of albumin is believed to be important for evaluating the blood concentration of ITCZ.