Phospholipidosis in Neurons Caused by Posaconazole, without Evidence for Functional Neurologic Effects

Abstract

The azole antifungal drug posaconazole caused phospholipidosis in neurons of the central nervous system, dorsal root ganglia of the spinal cord, and myenteric plexus in chronic toxicity studies in dogs. The time of onset, light and electron microscopic features, neurologic and electrophysiologic effects on the central and peripheral nervous systems, and potential for regression were investigated in a series of studies with a duration of up to one year. Nuclei of the medulla oblongata were the prominently affected areas of the brain. Neurons contained cytoplasmic vacuoles with concentrically whorled plasma membrane-like material (i.e., multilamellar bodies) morphologically identical to that commonly caused in other tissues by cationic amphiphilic drugs. Some axons in the brain and spinal cord were swollen and contained granular eosinophilic, electron-dense lysosomes. There were no features suggesting degeneration or necrosis of neurons or any associated elements of nervous tissue. The earliest and most consistent onset was in neurons of dorsal root ganglia. The observed neural phospholipidosis did not result in any alteration in the amplitude or latency of the auditory, visual, or somatosensory evoked potentials. The histopathologic changes did not progress or regress within the three-month postdose period. The results indicate that phospholipidosis can be induced in central and peripheral neurons of dogs by administration of posaconazole, but this change is not associated with functional effects in the systems evaluated.

Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment

“…Although the brain is a less commonly reported site of DIPL, azithromycin, chloroquine, quinacrine, 4,4′-diethylaminoethoxyhexestrol, chlorphentermine, iprindole, 1-chloro-amitriptyline, clomipramine, perhexiline, and fenfluramine have all been reported to cause DIPL in the rat brain and/or peripheral ganglia (Dastur et al, 1985;Frish and Lüllmann-Rauch, 1980;Lüllmann-Rauch, 1976;Jung and Suzuki, 1978). Posaconazole caused DIPL in the neurons of the CNS, dorsal root ganglia of the spinal cord and myenteric plexus in a toxicity study in dogs (Cartwright et al, 2009). In dogs treated with posaconazole, neurons contained multi-lamellar bodies and some axons in the brain and spinal cord were swollen and contained granular eosinophilic, electron dense lysosomes.…”

Visual Hallucinations Associated with High Posaconazole Concentrations in Serum

“…Posaconazole also binds CYP46A1 and may therefore also inhibit these pathways (7,8). Moreover, phospholipidosis due to membrane accumulation of posaconazole has been reported (9). Although central nervous system (CNS) toxicity has not previously been reported with posaconazole, this observation may reflect the low levels achieved with the oral suspension combined with its low CNS penetration (7,10).…”

Pathology and Neurotoxicity in Dogs after Repeat Dose Exposure to a Serotonin 5-HT_1B Inhibitor

“…Clearly, there are differences in the physical and chemical properties between AZD3783 and these aforementioned CADs that contributed to the differences in the toxicity and pathologic findings in the nervous tissues. One notable difference is that, in the study with posaconazole 28 inflammatory changes were not observed in any tissues with PLD. In contrast, in our studies with AZD3783, inflammation and gliosis was present in the nervous tissue (eye, ganglion, and brain).…”

“…Among the non-CNS drugs, posaconazole (an antifungal) caused PLD in DRG and medulla oblongata neurons in the brain of dogs after chronic administration. However, there was no evidence of neuronal degeneration or necrosis, nor was there any alteration in the amplitude, or latency of the auditory, visual, or somatosensory evoked potentials 28 . Clearly, there are differences in the physical and chemical properties between AZD3783 and these aforementioned CADs that contributed to the differences in the toxicity and pathologic findings in the nervous tissues.…”

“…This pattern of morphologic changes suggests that vacuolation due to PLD is a leading event to the degeneration or necrosis. PLD in the brain, nerves, or peripheral ganglia has not been reported with very many chemicals 28 . Even among antidepressant drugs or drug candidates, which as a class has the highest potential to induce generalized PLD 29 , few were reported to cause widespread PLD in the nervous system.…”