crossmark LETTER TO THE EDITOR
Visual Hallucinations Associated with High Posaconazole Concentrations in Serum Leighanne O. Parkes, Matthew P. Cheng, Donald C. Sheppard Division of Infectious Diseases and Department of Medical Microbiology, McGill University Health Centre, Montreal, Canada
P
osaconazole is a triazole used for the prevention and treatment of fungal infections. Unlike other mold-active azoles, posaconazole is generally well tolerated. Dose-dependent toxicity was not identified during the registration trials of the intravenous and tablet formulations, and levels in serum as high as 3.35 g/ml were observed (1, 2). We present herein the first case of visual hallucinations and neurological disturbances associated with extremely high levels of posaconazole in a patient undergoing treatment for chronic pulmonary aspergillosis (CPA). The patient is a 37-kg, 69-year-old female known to have chronic obstructive pulmonary disease. She was diagnosed with CPA in March 2014 and was treated with itraconazole at 200 mg per os (p.o.) twice a day (BID) for 11 months. In May 2015, voriconazole at 200 mg p.o. BID was initiated for treatment of a clinical and radiological relapse of her disease. After 1 week of voriconazole therapy, she presented to our hospital with acute complaints of disturbing visual hallucinations, including menacing miniature people. A medication review revealed no known drug-drug interactions associated with hallucinations. Voriconazole levels were not measured, but a diagnosis of voriconazoleassociated visual toxicity was made, her therapy was changed to posaconazole in oral suspension (200 mg p.o. four times a day [QID]), and her visual hallucinations resolved over 10 days. One month later, the posaconazole suspension was changed to the tablet formulation at 300 mg p.o. daily for improved tolerability. Five days later, she developed an acute recurrence of similar visual hallucinations, altered mental status, and symptoms of parkinsonism. A posaconazole trough level was 10.10 g/ml, which is, to our knowledge, the highest reported level of this agent in serum. Posaconazole tablets were discontinued, and her symptoms resolved with decreasing levels of posaconazole in serum
(Table 1). Posaconazole suspension at 200 mg p.o. BID was initiated without symptom recurrence. Visual and neurological disturbances are well-described adverse effects associated with voriconazole (3, 4). Although the exact mechanism remains unclear, it has been suggested that voriconazole-mediated inhibition of CYP46A1 leads to reduced 24S-hydroxycholesterol levels in retinal and neural cells, disrupting cholesterol homeostasis and membrane function (5). Alternatively, data from mouse models suggest that visual disturbances may result from voriconazole-mediated inhibition of transient receptor potential cation subunit M (TRPM1 and TRPM3) channels within retinal and neural cells (6). 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). However, newer formulations result in significantly higher posaconazole concentrations in serum (11), particularly in patients with low body mass (12). Use of posaconazole tablets can result in serum concentrations above the range that has been well
Accepted manuscript posted online 7 December 2015 Citation Parkes LO, Cheng MP, Sheppard DC. 2016. Visual hallucinations associated with high posaconazole concentrations in serum. Antimicrob Agents Chemother 60:1170 –1171. doi:10.1128/AAC.02739-15. Address correspondence to Leighanne O. Parkes, [email protected]. Copyright © 2016, American Society for Microbiology. All Rights Reserved.
TABLE 1 Dates and treatments for a 37-kg, 69-year-old female with CPA Date
Antifungal treatment
21 May 2014 26 February 2015 4 June 2015 11 June 2015 18 June 2015 18 June 2015 4 August 2015 9 August 2015
Itraconazole (200 mg p.o. BID) started Itraconazole stopped Voriconazole (200 mg p.o. BID) started Voriconazole (200 mg p.o. BID) Voriconazole stopped Posaconazole suspension (200 mg p.o. QID) Posaconazole tablets (300 mg p.o. daily) started Posaconazole tablets (300 mg p.o. daily)
13 August 2015
Posaconazole tablets (300 mg p.o. daily)
10.10
20 August 2015 28 August 2015 29 August 2015 31 August 2015
Posaconazole held Posaconazole held Posaconazole suspension (200 mg p.o. BID) started Posaconazole suspension (200 mg p.o. BID)
5.47 0.17
1170
aac.asm.org
Posaconazole level (g/ml)
0.64
Antimicrobial Agents and Chemotherapy
Feature(s) of toxicity Asymptomatic Asymptomatic Asymptomatic Visual hallucination Visual hallucination Improving visual hallucination Asymptomatic Visual hallucination, cogwheeling, postural hypotension, dysphagia, cognitive impairment Visual hallucination, cogwheeling, postural hypotension, dysphagia, cognitive impairment Improving symptoms No neurological signs or symptoms No neurological signs or symptoms No neurological signs or symptoms
February 2016 Volume 60 Number 2
Letter to the Editor
studied for tolerability, although a toxicity-exposure relationship has yet to be established (13). Thus, patients receiving new formulations of posaconazole should be monitored for visual, CNS, and other novel toxicities, and therapeutic drug monitoring should be performed upon suspicion of toxicity and in patients with low body mass. ACKNOWLEDGMENTS We declare that we have no conflicts of interest relevant to this letter. Donald C. Sheppard is a member of the speaker bureaus of MSD and Pfizer and is a member of the advisory board of MSD. He has also received research support from MSD. Full disclosures are available upon request.
REFERENCES 1. Maertens J, Cornely OA, Ullmann AJ, Heinz WJ, Krishna G, Patino H, Caceres M, Kartsonis N, Waskin H, Robertson MN. 2014. Phase 1B study of the pharmacokinetics and safety of posaconazole intravenous solution in patients at risk for invasive fungal disease. Antimicrob Agents Chemother 58:3610 –3617. http://dx.doi.org/10.1128/AAC.02686-13. 2. Duarte RF, Lopez-Jimenez J, Cornely OA, Laverdiere M, Helfgott D, Haider S, Chandrasekar P, Langston A, Perfect J, Ma L, van Iersel ML, Connelly N, Kartonsonis N, Waskin H. 2014. Phase 1B study of new posaconazole tablet for prevention of invasive fungal infections in highrisk patients with neutropenia. Antimicrob Agents Chemother 58:5758 – 5765. http://dx.doi.org/10.1128/AAC.03050-14. 3. Johnson LB, Kauffman CA. 2003. Voriconazole: a new triazole antifungal agent. Clin Infect Dis 36:630 – 637. http://dx.doi.org/10.1086/367933. 4. Seyedmousavi S, Mouton JW, Verweij PE, Bruggemann RJM. 2013. Therapeutic drug monitoring of voriconazole and posaconazole for invasive aspergillosis. Expert Rev Anti Infect Ther 11:931–941. http://dx.doi .org/10.1586/14787210.2013.826989. 5. Mast N, Annalora AJ, Lodowski DT, Palczewski K, Stout CD, Pikuleva IA. 2010. Structural basis of drug binding to CYP46A1, an enzyme that controls cholesterol turnover in the brain. J Biol Chem 285:31783–31795. http://dx.doi.org/10.1074/jbc.M110.143313.
February 2016 Volume 60 Number 2
6. Xiong WH, Brown RL, Reed B, Burke NS, Duvoisin RM, Morgans CW. 2015. Voriconazole, an antifungal triazol that causes visual side effects, is an inhibitor of TRPM1 and TRPM3 channels. Invest Ophthalmol Vis Sci 56:1367–1373. http://dx.doi.org/10.1167/iovs.14-15270. 7. Ruping MJ, Albermann N, Ebinger F, Burckhardt I, Beisel C, Muller C, Vehreschild JJ, Kochanek M, Fatkenheuer G, Bangard C, Ullmann AJ, Herr W, Kolbe K, Hallek M, Cornely OA. 2008. Posaconazole concentrations in the central nervous system. J Antimicrob Chemother 62:1468 – 1470. http://dx.doi.org/10.1093/jac/dkn409. 8. Mast N, Zheng W, David Stout C, Pikuleva IA. 2013. Antifungal azoles: structural insights into the undesired tight binding to cholesterolmetabolizing CYP46A1. Mol Pharmacol 84:86 –94. http://dx.doi.org/10 .1124/mol.113.085902. 9. Cartwright ME, Petruska J, Arezzo J, Frank D, Litwak M, Morrissey RE, MacDonald J, Davis TE. 2009. Phospholipidosis in neurons caused by posaconazole, without evidence for functional neurological effects. Toxicol Pathol 37:902–910. http://dx.doi.org/10.1177/019262 3309348521. 10. Courtney R, Pai S, Laughlin M, Lim J, Batra V. 2003. Pharmacokinetics, safety and tolerability of oral posaconazole administered in single and multiple doses in healthy adults. Antimicrob Agents Chemother 47:2788 – 2795. http://dx.doi.org/10.1128/AAC.47.9.2788-2795.2003. 11. Cumpston A, Caddell R, Shillingburg A, Lu X, Wen S, Hamadani M, Craig M, Kanate AS. 2015. Superior serum concentrations with posaconazole delayed-release tablets compared to suspension formulation in hematological malignancies. Antimicrob Agents Chemother 59:4424 – 4428. http://dx.doi.org/10.1128/AAC.00581-15. 12. Miceli MH, Perissinotti AJ, Jauffman CA, Couriel DR. 2015. Serum posaconazole levels among haematological cancer patients taking extended release tablets is effected by body weight and diarrhoea: single centre retrospective analysis. Mycoses 58:432– 436. http://dx.doi.org/10 .1111/myc.12339. 13. Pettit NN, Steinbeck JL, Han J. 2014. Posaconazole tablet formulation therapeutic drug monitoring and toxicity analysis, abstr A-702. Prog Abstr 54th Intersci Conf Antimicrob Agents Chemother. American Society for Microbiology, Washington, DC.
Antimicrobial Agents and Chemotherapy
aac.asm.org
1171
Visual Hallucinations Associated with High Posaconazole Concentrations in Serum Leighanne O. Parkes, Matthew P. Cheng, Donald C. Sheppard Division of Infectious Diseases and Department of Medical Microbiology, McGill University Health Centre, Montreal, Canada
P
osaconazole is a triazole used for the prevention and treatment of fungal infections. Unlike other mold-active azoles, posaconazole is generally well tolerated. Dose-dependent toxicity was not identified during the registration trials of the intravenous and tablet formulations, and levels in serum as high as 3.35 g/ml were observed (1, 2). We present herein the first case of visual hallucinations and neurological disturbances associated with extremely high levels of posaconazole in a patient undergoing treatment for chronic pulmonary aspergillosis (CPA). The patient is a 37-kg, 69-year-old female known to have chronic obstructive pulmonary disease. She was diagnosed with CPA in March 2014 and was treated with itraconazole at 200 mg per os (p.o.) twice a day (BID) for 11 months. In May 2015, voriconazole at 200 mg p.o. BID was initiated for treatment of a clinical and radiological relapse of her disease. After 1 week of voriconazole therapy, she presented to our hospital with acute complaints of disturbing visual hallucinations, including menacing miniature people. A medication review revealed no known drug-drug interactions associated with hallucinations. Voriconazole levels were not measured, but a diagnosis of voriconazoleassociated visual toxicity was made, her therapy was changed to posaconazole in oral suspension (200 mg p.o. four times a day [QID]), and her visual hallucinations resolved over 10 days. One month later, the posaconazole suspension was changed to the tablet formulation at 300 mg p.o. daily for improved tolerability. Five days later, she developed an acute recurrence of similar visual hallucinations, altered mental status, and symptoms of parkinsonism. A posaconazole trough level was 10.10 g/ml, which is, to our knowledge, the highest reported level of this agent in serum. Posaconazole tablets were discontinued, and her symptoms resolved with decreasing levels of posaconazole in serum
(Table 1). Posaconazole suspension at 200 mg p.o. BID was initiated without symptom recurrence. Visual and neurological disturbances are well-described adverse effects associated with voriconazole (3, 4). Although the exact mechanism remains unclear, it has been suggested that voriconazole-mediated inhibition of CYP46A1 leads to reduced 24S-hydroxycholesterol levels in retinal and neural cells, disrupting cholesterol homeostasis and membrane function (5). Alternatively, data from mouse models suggest that visual disturbances may result from voriconazole-mediated inhibition of transient receptor potential cation subunit M (TRPM1 and TRPM3) channels within retinal and neural cells (6). 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). However, newer formulations result in significantly higher posaconazole concentrations in serum (11), particularly in patients with low body mass (12). Use of posaconazole tablets can result in serum concentrations above the range that has been well
Accepted manuscript posted online 7 December 2015 Citation Parkes LO, Cheng MP, Sheppard DC. 2016. Visual hallucinations associated with high posaconazole concentrations in serum. Antimicrob Agents Chemother 60:1170 –1171. doi:10.1128/AAC.02739-15. Address correspondence to Leighanne O. Parkes, [email protected]. Copyright © 2016, American Society for Microbiology. All Rights Reserved.
TABLE 1 Dates and treatments for a 37-kg, 69-year-old female with CPA Date
Antifungal treatment
21 May 2014 26 February 2015 4 June 2015 11 June 2015 18 June 2015 18 June 2015 4 August 2015 9 August 2015
Itraconazole (200 mg p.o. BID) started Itraconazole stopped Voriconazole (200 mg p.o. BID) started Voriconazole (200 mg p.o. BID) Voriconazole stopped Posaconazole suspension (200 mg p.o. QID) Posaconazole tablets (300 mg p.o. daily) started Posaconazole tablets (300 mg p.o. daily)
13 August 2015
Posaconazole tablets (300 mg p.o. daily)
10.10
20 August 2015 28 August 2015 29 August 2015 31 August 2015
Posaconazole held Posaconazole held Posaconazole suspension (200 mg p.o. BID) started Posaconazole suspension (200 mg p.o. BID)
5.47 0.17
1170
aac.asm.org
Posaconazole level (g/ml)
0.64
Antimicrobial Agents and Chemotherapy
Feature(s) of toxicity Asymptomatic Asymptomatic Asymptomatic Visual hallucination Visual hallucination Improving visual hallucination Asymptomatic Visual hallucination, cogwheeling, postural hypotension, dysphagia, cognitive impairment Visual hallucination, cogwheeling, postural hypotension, dysphagia, cognitive impairment Improving symptoms No neurological signs or symptoms No neurological signs or symptoms No neurological signs or symptoms
February 2016 Volume 60 Number 2
Letter to the Editor
studied for tolerability, although a toxicity-exposure relationship has yet to be established (13). Thus, patients receiving new formulations of posaconazole should be monitored for visual, CNS, and other novel toxicities, and therapeutic drug monitoring should be performed upon suspicion of toxicity and in patients with low body mass. ACKNOWLEDGMENTS We declare that we have no conflicts of interest relevant to this letter. Donald C. Sheppard is a member of the speaker bureaus of MSD and Pfizer and is a member of the advisory board of MSD. He has also received research support from MSD. Full disclosures are available upon request.
REFERENCES 1. Maertens J, Cornely OA, Ullmann AJ, Heinz WJ, Krishna G, Patino H, Caceres M, Kartsonis N, Waskin H, Robertson MN. 2014. Phase 1B study of the pharmacokinetics and safety of posaconazole intravenous solution in patients at risk for invasive fungal disease. Antimicrob Agents Chemother 58:3610 –3617. http://dx.doi.org/10.1128/AAC.02686-13. 2. Duarte RF, Lopez-Jimenez J, Cornely OA, Laverdiere M, Helfgott D, Haider S, Chandrasekar P, Langston A, Perfect J, Ma L, van Iersel ML, Connelly N, Kartonsonis N, Waskin H. 2014. Phase 1B study of new posaconazole tablet for prevention of invasive fungal infections in highrisk patients with neutropenia. Antimicrob Agents Chemother 58:5758 – 5765. http://dx.doi.org/10.1128/AAC.03050-14. 3. Johnson LB, Kauffman CA. 2003. Voriconazole: a new triazole antifungal agent. Clin Infect Dis 36:630 – 637. http://dx.doi.org/10.1086/367933. 4. Seyedmousavi S, Mouton JW, Verweij PE, Bruggemann RJM. 2013. Therapeutic drug monitoring of voriconazole and posaconazole for invasive aspergillosis. Expert Rev Anti Infect Ther 11:931–941. http://dx.doi .org/10.1586/14787210.2013.826989. 5. Mast N, Annalora AJ, Lodowski DT, Palczewski K, Stout CD, Pikuleva IA. 2010. Structural basis of drug binding to CYP46A1, an enzyme that controls cholesterol turnover in the brain. J Biol Chem 285:31783–31795. http://dx.doi.org/10.1074/jbc.M110.143313.
February 2016 Volume 60 Number 2
6. Xiong WH, Brown RL, Reed B, Burke NS, Duvoisin RM, Morgans CW. 2015. Voriconazole, an antifungal triazol that causes visual side effects, is an inhibitor of TRPM1 and TRPM3 channels. Invest Ophthalmol Vis Sci 56:1367–1373. http://dx.doi.org/10.1167/iovs.14-15270. 7. Ruping MJ, Albermann N, Ebinger F, Burckhardt I, Beisel C, Muller C, Vehreschild JJ, Kochanek M, Fatkenheuer G, Bangard C, Ullmann AJ, Herr W, Kolbe K, Hallek M, Cornely OA. 2008. Posaconazole concentrations in the central nervous system. J Antimicrob Chemother 62:1468 – 1470. http://dx.doi.org/10.1093/jac/dkn409. 8. Mast N, Zheng W, David Stout C, Pikuleva IA. 2013. Antifungal azoles: structural insights into the undesired tight binding to cholesterolmetabolizing CYP46A1. Mol Pharmacol 84:86 –94. http://dx.doi.org/10 .1124/mol.113.085902. 9. Cartwright ME, Petruska J, Arezzo J, Frank D, Litwak M, Morrissey RE, MacDonald J, Davis TE. 2009. Phospholipidosis in neurons caused by posaconazole, without evidence for functional neurological effects. Toxicol Pathol 37:902–910. http://dx.doi.org/10.1177/019262 3309348521. 10. Courtney R, Pai S, Laughlin M, Lim J, Batra V. 2003. Pharmacokinetics, safety and tolerability of oral posaconazole administered in single and multiple doses in healthy adults. Antimicrob Agents Chemother 47:2788 – 2795. http://dx.doi.org/10.1128/AAC.47.9.2788-2795.2003. 11. Cumpston A, Caddell R, Shillingburg A, Lu X, Wen S, Hamadani M, Craig M, Kanate AS. 2015. Superior serum concentrations with posaconazole delayed-release tablets compared to suspension formulation in hematological malignancies. Antimicrob Agents Chemother 59:4424 – 4428. http://dx.doi.org/10.1128/AAC.00581-15. 12. Miceli MH, Perissinotti AJ, Jauffman CA, Couriel DR. 2015. Serum posaconazole levels among haematological cancer patients taking extended release tablets is effected by body weight and diarrhoea: single centre retrospective analysis. Mycoses 58:432– 436. http://dx.doi.org/10 .1111/myc.12339. 13. Pettit NN, Steinbeck JL, Han J. 2014. Posaconazole tablet formulation therapeutic drug monitoring and toxicity analysis, abstr A-702. Prog Abstr 54th Intersci Conf Antimicrob Agents Chemother. American Society for Microbiology, Washington, DC.
Antimicrobial Agents and Chemotherapy
aac.asm.org
1171
