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Persistent CNS toxicity in a patient receiving posaconazole tablets after discontinuation of voriconazole due to supratherapeutic serum levels

Year: 2017
Type: article
Abstract: Sir, The new triazoles voriconazole and posaconazole are frequently used for the management of fungal infections in patients with haematological malignancies and HSCT. CNS toxicities with voriconazole are well described and are correlated with high (>5.5 mg/L) voriconazole serum levels, yet the use of posaconazole suspension has not been associated with CNS toxicity.1,2 The recently introduced delayed-release (DR) tablet formulation of posaconazole overcomes the poor bioavailability issues seen with the suspension.2,3 The frequency of CNS toxicity with posaconazole DR tablets, which achieve higher serum drug levels, is presently unknown. A recent case reported CNS toxicity associated with posaconazole serum levels >10000 ng/mL in a cachectic patient taking the tablet formulation; toxicities were alleviated after the patient was switched back to the suspension formulation, with resulting lower serum levels.4 We present here a case of persistently altered mental status (AMS) and encephalopathy in a patient who was transitioned from supratherapeutic voriconazole to DR posaconazole. The patient was a profoundly neutropenic 62 kg, 56-year-old male with AML, which relapsed 7 months (November 2015) following a double-cord HSCT. The patient had been on chronic oral voriconazole 200 mg twice daily as antifungal prophylaxis, which was well tolerated and without toxicity. In November 2016 [day 1 (D1)], he was admitted for new-onset jaw swelling with right mandibular cellulitis. On D8, he developed rapid-onset AMS. All potentially neurotoxic medications, including cefepime, sedatives and voriconazole, were withheld. The patient was started on liposomal amphotericin B at 5 mg/kg/day. A CT scan of the head, an MRI scan of the brain and electroencephalogram (EEG) were unrevealing. The voriconazole serum level measured that day, 29 h after the last administered dose, was 4.2 mg/L, suggesting that a true 12 h trough value may have been supratherapeutic. Voriconazole was stopped until D11, when liposomal amphotericin B was stopped and voriconazole was resumed as the intravenous formulation at 6 mg/kg for two loading doses, followed by 4 mg/kg every 12 h. Other potentially neurotoxic medications continued to be withheld. On D14 the patient was transitioned from voriconazole to posaconazole DR tablets (300 mg/day) and intravenous caspofungin (50 mg/day) after biopsy of the maxillary sinus was consistent with invasive mucormycosis. Due to persistent AMS, the voriconazole serum level was measured again and a 5 h level was found to be supratherapeutic at 9.0 mg/L. Continued worsening AMS led to a repeat MRI scan of the brain on D15 that revealed no abnormalities, such as cavernous sinus thrombosis or intracranial abscess/bleeding, to implicate mucormycosis as the cause of the AMS. Liposomal amphotericin B was resumed on D18. Lumbar puncture on D19 also indicated no abnormalities. Neuro-oncology was consulted and believed the changes in mental status were likely due to toxic metabolic encephalopathy secondary to medication use, likely azoles. The patient’s AMS waxed and waned until D26, when he began to show initial improvement. Unresolved AMS led to the discontinuation of posaconazole on D28, and subsequently the serum level from that day measured 20 h after the last dose was found to be 3650 ng/mL, with a concurrent voriconazole serum level of <0.1 mg/L. Following the discontinuation of posaconazole, the patient had prompt resolution of AMS. He was continued on liposomal amphotericin B for his invasive fungal sinusitis. Notably, on D48, 300 mg posaconazole DR tablets were resumed and the patient tolerated this therapy without CNS complications. Table 1 depicts the sequence of azole administration, the serum levels and the evolution of AMS. Timeline of treatments and clinical status of patient with AMS due to azole toxicity po, by mouth. Timeline of treatments and clinical status of patient with AMS due to azole toxicity po, by mouth. In our recent experience at MD Anderson Cancer Center, over 15% of patients on posaconazole DR tablets had serum levels >4000 ng/mL without apparent CNS toxicity, suggesting that higher levels alone are not predictive of CNS toxicities.5 We hypothesize that our patient experienced synergistic triazole toxicity while on posaconazole due to concurrent supratherapeutic voriconazole serum levels. We hypothesize that, as a substrate of CYP3A4, voriconazole metabolism may have been inhibited by the initiation of posaconazole, a potent CYP3A4 inhibitor, potentially resulting in prolonged voriconazole exposure despite its discontinuation. However, AMS did not resolve until posaconazole was discontinued, even at low voriconazole levels. Posaconazole-induced phospholipidosis in neurons has been reported, but the potential mechanisms behind posaconazole CNS toxicity remain to be elucidated.6 The fact that CNS toxicity did not occur on posaconazole rechallenge supports the notion that posaconazole DR tablets may be associated with CNS effects through lowering of a neurotoxicity threshold by concurrent exposure to other CNS-compromising agents such as voriconazole. In conclusion, use of posaconazole DR tablets may be associated with CNS effects when the toxicity threshold is lowered by concurrent exposure to other CNS-compromising agents such as voriconazole at supratherapeutic concentrations. This study was supported by internal funding. D. P. K. has received research support from Pfizer and Astellas, and has received honoraria from Merck, Astellas, Pfizer and Amplyx, Inc. F. F.: none to declare.
DOI: 10.1093/jac/dkx362
Language: English
Field: Medicine
Open Access status: bronze
OpenAlex ID: W2763681245
FWCI: 0.975
Cites: 5
Cited by: 8
Related to: 10