Table of Contents  
CASE REPORT
Year : 2013  |  Volume : 4  |  Issue : 4  |  Page : 294-297  

Elevation of blood ciclosporin levels by voriconazole leading to leukoencephalopathy


1 Department of Clinical Pharmacology, the Third Affiliated Hospital of Sun Yat-sen University, Tianhe Road, Guangzhou, China
2 Department of Radiology, the Third Affiliated Hospital of Sun Yat-sen University, Tianhe Road, Guangzhou, China
3 Department of Internal Medicine, the Third Affiliated Hospital of Sun Yat-sen University, Tianhe Road, Guangzhou, China

Date of Web Publication10-Oct-2013

Correspondence Address:
Qu Caihong
Department of Clinical Pharmacology, the Third Affiliated Hospital of Sun Yat-sen University, Tianhe Road, Guangzhou
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0976-500X.119721

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   Abstract 

We report that one 18-year-old female patient with no epilepsia history developed severe epileptiform seizures while she was receiving "ciclosporin A (CsA)-mycophenolate-methylprednisolone" antirejection therapy after combining one week's voriconazole administration following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndromes (MDS). Her blood concentration of CsA was 378 ng/ml (elevated ↑64%, contrasted with the level before the addition of voriconazole) on the second day of admission, and the MRI of head showed leukoencephalopathy in bilateral occipital and left frontal lobe on the 4 th day of admission. The most likely mechanism is that because of voriconazole's enzyme inhibition and CsA as the substrate of hepatic enzymes, voriconazole elevated the blood concentration of CsA and enhanced its toxicity. This case highlights the importance of clinical pharmacists joining the medical team and optimizing the patients' treatment protocols by performing a systematic literature research, accumulating the knowledge of the potential drug interaction and examining prescriptions.

Keywords: CsA, drug-drug interaction, eleptiform seizures, leukoencephalopathy, voriconazole


How to cite this article:
Caihong Q, Weimin L, Jieming Z. Elevation of blood ciclosporin levels by voriconazole leading to leukoencephalopathy. J Pharmacol Pharmacother 2013;4:294-7

How to cite this URL:
Caihong Q, Weimin L, Jieming Z. Elevation of blood ciclosporin levels by voriconazole leading to leukoencephalopathy. J Pharmacol Pharmacother [serial online] 2013 [cited 2019 Jul 21];4:294-7. Available from: http://www.jpharmacol.com/text.asp?2013/4/4/294/119721


   Introduction Top


Ciclosporin A (CsA) is used to treat and prevent rejection and graft-versus-host disease (GVHD) after solid organ transplantation (SOT) as well as hematopoietic stem cell transplantation (HSCT). [1],[2] Voriconazole is frequently used in HSCT or SOT recipients for prevention or treatment of invasive fungal infections (IFIs). Because voriconazole can inhibit the P450 enzyme system potently, it has many potential drug interactions. The interaction between voriconazole and CsA may result in the enhancement of the toxicity of CsA. Here, we report one case in which one 18-year-old female patient of allogeneic HSCT without epilepsia history developed headache, dizziness, blurred vision, and worsened to epileptiform seizures on the 70 th day postoperative when she was receiving "CsA-mycophenolate-methylprednisolone" antirejection in case of combination with one week's voriconazole administration. Her blood concentration of CsA was 378 ng/ml (elevated ↑64%, contrasted with the average level before the addition of voriconazole) on the second day of admission. Therefore, interaction between voriconazole and CsA was suspected.


   Case Report Top


One 18-year-old 46-kg female patient was admitted on the 70 th day postoperative with complaints of dizziness, headaches, and blurred vision for 2 days. Her consciousness was distinct without nausea, vomiting, cough, expectoration, urinary, or fecal incontinence on admission. Her vital signs suggested normal body temperature and normal blood pressure with heart rate (HR) of 98 bpm. Examination of ocular fundus was normal. She did not have pre-existing neurological disorders and had not received significant amounts of psychotropic drugs before. Her medication history revealed that she was receiving "CsA (100 mg, q12h, po)-mycophenolate (1g, q12h, po)-methylprednisolone (8 mg, q12h, po)" antirejection therapy, because she had received allogeneic HSCT for myelodysplastic syndromes (MDS) 70 days before. The patient suffered from coughing accompanying expectoration 14 days ago, and the chest computed tomography (CT) showed pulmonary infections in the superior lobe of right lung. Cefaclor sustained release table had been administrated for one week, however symptoms did not improve. Fungus infection was suspected. Tablet voriconazole (400 mg, q12h, po) on the first day, followed by 200 mg every 12 h orally was added for the prophylaxis of IFI one week later. During this period, other medications, including herbal remedies and vitamins, had not been used; her liver function and renal function tests during the past 2 months were normal. After admission carbamazepine, rotundine, and citicoline sodium were administrated immediately for symptomatic treatment and supportive management; however, her condition continued to deteriorate in the next 2 hours, she dropped into locked jaw and convulsion of limbs, presented with epileptiform seizures, which was gradually improved by 10 mg diazepam (once) and 7 days of phenobarbital (0.1 g, bid, im) afterwards.

A standard fluorescence polarization immunoassay (FPIA) was used to detect the trough blood concentration of CsA before the next administration. Historical trough whole blood concentration of CsA (reference range 150-300 ng/ml) was collected within the past month (average 230 ng/ml) before the combination with voriconazole. On the second day of admission, the blood concentration of CsA was 378 ng/ml. On the same day other examinations such as blood counts, cerebrospinal fluid, and serum chemistries are shown in [Table 1]. Blood smear showed plenty of leukocytes which were well distributed, and the immunochemical assay for cytomegalovirus (CMV) showed negative result on the third day of admission, the chest CT showed inflammation in anterior segment of superior lobe and median lobe in the right lung on the same day. Magnetic resonance imaging (MRI) of head showed leukoencephalopathy in bilateral occipital and left frontal lobe on the 4 th day of admission.
Table 1: Laboratory data on the second day of admission

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According to the clinical symptoms, laboratory examinations, and imaging examinations, the interaction between CsA and voriconazole was suspected. The concentration of CsA had risen slowly to 378 ng/ml during the past 7 days of co-administration with voriconazole. So voriconazole was suspended, and alprostadil, clopidogrel, and atorvastatin were administered from the second day of hospital stay to improve microcirculation and decrease hyperlipemia. From the third day of hospital stay, cefoperazone sodium and sulbactam sodium for injection were added to control the inflammation in the right lung. Her condition improved gradually. Because of the phenobarbital's induction of enzymes, the blood concentration of CsA dropped to 57 ng/ml on the 8 th day of hospital stay; therefore, phenobarbital was suspended after 7 days' medication under the circumstances of improved neurologic signs. On the 9 th day of admission, the CT in chest showed amelioration in superior lobe of right lung comparing to anterior results besides miliary tuberosity in bilateral lungs, probable fungus infection, and the 1-3-β-D polyglucosan elevated to 89.57 pg/ml on the 10 th day of admission. Voriconazole treatment was administered again to control fungus infection in bilateral lungs. To prevent drug toxicity, the dose of CsA was adjusted to 3/4 compared to the initial dose. Satisfactory steady-state blood concentration of CsA was achieved (250 ng/ml around). She was discharged 12 days later. The trough concentration of CsA and the important co-administered drugs (including enzyme inhibitors or enzyme inductors) during different time periods are shown in [Table 2].
Table 2: The change of CsA trough concentration with the combination of voriconazole or phenobarbital

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   Discussion Top


Voriconazole and its metabolites are inhibitors of CYP450 liver enzymes, including CYP2C9, CYP2C19, and CYP3A4 isoenzymes. CsA, a calcineurin inhibitor, is a substrate for CYP450 enzymes. Voriconazole can inhibit the metabolism of CsA and prolong its action. The interaction between voriconazole and CsA can cause unexpected adverse effects even under standard therapeutic doses. According to Naranjo Adverse Drug Reaction Probability Scale (NADRS), the score of this severe adverse drug reaction (ADR) is 6, which indicates a probable ADR due to the drug-drug interaction (DDI) between voriconazole and CsA. This score is based on the following points: First, the studies on the DDI between voriconazole and CsA have been reported and widely recognized; second, the ADR occurred after voriconazole was administrated with the presentation of dizziness, headaches, blurred vision, locked jaw, convulsion of limbs, and elevated blood concentration of CsA (↑64%); third, the ADR improved by discontinuing voriconazole, administering 7 days' phenobarbital as specific treatment, other symptomatic treatment, and supportive management for epileptiform seizures; fourth, the patient did not have pre-existing neurological disorders or epilepsia history; and the last, in this patient, the possibility of mycophenalate and methylprednisolone causing neuropathy are scarce and lack of monitoring of its blood concentration; though voriconazole can also cause tremor, dizziness, and disordered vision, but convulsion and encephalopathy associated with voriconazole are a rare phenomena. Therefore, the possibility of the ADR associated with other co-administrated drugs was low. To sum up, we inferred that epileptiform seizures were induced by leukoencephalopathy in bilateral occipital and left frontal lobe, leukoencephalopathy was caused by the elevation of blood concentration of CsA, and the elevation of the blood concentration of CsA was induced by enzyme inhibition of voriconazole.

According to literature, neurotoxicity of CsA may be different, which may display arterial hypertension, headache, visual disturbances, hemiparesis, [3],[4]  Parkinsonism More Details, [5] leukoencephalopathy, and so on. [6],[7] Its possible reason is that CsA can permeate the blood brain barrier and impact on mitochondrial function in endothelial cells. [8] These pathological changes are reversible, which can relieve gradually or disappear through lowering dosage, suspending, or changing to other immunosuppressive agents.

Since up to 21% of adverse drug event-related hospital admissions are due to drug interactions, [9] therapeutic drug monitoring (TDM) of CsA is necessary not only before and after combination with voriconazole treatment for safe and convenient modification of immunosuppressive agents, but also when voriconazole is not added in the regimen, and even if it is in standard therapeutic dose. [10] As several studies have shown the variable magnitude of DDI between voriconazole and CsA as well as the P-gp inhibition of voriconazole-mediated, [11],[12],[13] therefore, dose adjustment of CsA should be determined on an individual basis by closely monitoring the blood levels of CsA, and the concentration of CsA maintaining at a the low serum and high intracellular cyclosporine levels may contribute to an immunosuppressive state on initiating voriconazole administration.


   Conclusion Top


This case highlights the importance that clinical pharmacists should collaborate with the medical team by analyzing TDM results in case of integrating prescriptions and accumulating the knowledge of potential drug interaction through performing a systematic literature research. In this patient, the concentration of CsA increased from 230 to 378 ng/ml, with a percentage of 64% after initiating voriconazole, which presented headache, dizziness, blurred vision, and worsened to epileptiform seizures. Therefore, it is clinical pharmacists' responsibility to manage drug-drug interactions and optimize the patients' treatment protocols by tabling proposals to clinicians when it is necessary. This severe ADR caused by DDI between voriconazole and CsA has been reported to the national centre for ADR monitoring of China (registered as number 20100011) and evaluated as "probably".

 
   References Top

1.Cohen DJ, Loertscher R, Rubin MF, Tilney NL, Carpenter CB, Strom TB. Cyclosporine: A new immunosuppressive agent for organ transplantation. Ann Intern Med 1984;101:667-82.  Back to cited text no. 1
    
2.Willemze AJ, Cremers SC, Schoemaker RC, Lankester AC, den Hartigh J, Burggraaf J, et al. Ciclosporin kinetics in children after stem cell transplantation. Br J Clin Pharmacol 2008;66:539-45.  Back to cited text no. 2
    
3.Shah AK. Cyclosporine A neurotoxicity among bone marrow transplant recipients. Clin Neuropharmacol 1999;22:67-73.  Back to cited text no. 3
    
4.Trullemans F, Grignard F, Van Camp B, Schots R. Clinical findings and magnetic resonance imaging in severe cyclosporine-related neurotoxicity after allogeneic bone marrow transplantation. Eur J Haematol 2001;67:94-9.  Back to cited text no. 4
    
5.Wasserstein PH, Honig LS. Parkinsonism during cyclosporine treatment. Bone Marrow Transplant 1996;18:649-50.  Back to cited text no. 5
    
6.Sakai N, Kawasaki Y, Imaizumi T, Imaizumi T, Kanno S, Go H, et al. Two patients with focal segmental glomerulosclerosis complicated by cyclosporine-induced reversible posterior leukoencephalopathy syndrome. Clin Nephrol 2010;73:482-6.  Back to cited text no. 6
    
7.Schacherer D, Zeitoun M, Buttner R, Gelbmann C, Obed A, Schlitt HJ, et al. Sirolimus-induced drug fever and ciclosporin-induced leukencephalopathia with seizures in one liver transplant recipient. World J Gastroenterol 2007;13:6090-3.  Back to cited text no. 7
    
8.Illsinger S, Janzen N, Lücke T, Bednarczyk J, Schmidt KH, Hoy L, et al. Cyclosporine A: Impact on mitochondrial function in endothelial cells. Clin Transplant 2011;25:584-93.  Back to cited text no. 8
    
9.Roughead EE, Kalisch LM, Barratt JD, Gilbert AL. Prevalence of potentially hazardous drug interactions amongst Australian veterans. Br J Clin Pharmacol 2010;70:252-7.  Back to cited text no. 9
    
10.Dodds-Ashley E. Management of drug and food interactions with azole antifungal agents in transplant recipients. Pharmacotherapy 2010;30:842-54.  Back to cited text no. 10
    
11.Park SJ, Song IS, Kang SW, Joo H, Kim TH, Yoon YC, et al. Pharmacokinetic effect of voriconazole on cyclosporine in the treatment of aspergillosis after renal transplantation. Clin Nephrol 2012;78:412-8.  Back to cited text no. 11
    
12.Mori T, Aisa Y, Kato J, Nakamura Y, Ikeda Y, Okamoto S. Drug interaction between voriconazole and calcineurin inhibitors in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 2009;44:371-4.  Back to cited text no. 12
    
13.Kikuchi T, Mori T, Yamane A, Kato J, Kohashi S, Okamoto S. Variable magnitude of drug interaction between oral voriconazole and cyclosporine A in recipients of allogeneic hematopoietic stem cell transplantation. Clin Transplant 2012;26:E544-8.  Back to cited text no. 13
    



 
 
    Tables

  [Table 1], [Table 2]


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