Medical Mycology Case Reports 2 (2013) 134–136
Contents lists available at ScienceDirect
Medical Mycology Case Reports journal homepage: www.elsevier.com/locate/mmcr
Therapeutic drug monitoring in voriconazole-associated hyponatremia Ren-ai Xu a,b, Shuang-li Zheng a, Li-li Xiao a, Xue-ding Cai b, Xi-xi Lai b, Guan-yang Lin b, Lu-feng Hu b, Chun-hong Zhang b, Zhi-sheng Xu a,n, Xiu-hua Zhang b,n a b
The Second Affiliated Hospital of Wenzhou Medical College, Wenzhou 325000, China The First Affiliated Hospital of Wenzhou Medical College, Wenzhou 325000, China
art ic l e i nf o
a b s t r a c t
Article history: Received 18 April 2013 Received in revised form 7 June 2013 Accepted 12 June 2013
Voriconazole is a second generation triazole antifungal agent and the first choice therapy for invasive aspergillosis (IA). Although voriconazole may be associated with many adverse events, hyponatremia has been rarely reported which potentially could result in death. Therapeutic drug monitoring (TDM) and individualization of therapy by measuring voriconazole plasma concentrations improved the efficacy and safety in patients. We report the effect of TDM to adjust voriconazole dosage in a voriconazole-related hyponatremia patient. & 2013 International Society for Human and Animal Mycology. Published by Elsevier B.V All rights reserved.
Keywords: Voriconazole Therapeutic drug monitoring Hyponatremia Invasive pulmonary aspergillosis
1. Introduction Invasive pulmonary aspergillosis (IPA) is a necrotizing pneumonia caused by airborne opportunistic fungi of Aspergillus species [1]. Its frequency increases in patients with Chronic Obstructive Pulmonary Disease (COPD), mainly when steroids are prescribed. Voriconazole is a second generation triazole antifungal agent and the first choice therapy for invasive aspergillosis (IA) [2]. Although voriconazole is generally well tolerated, anecdotal case reports have described unexpected severe adverse events related to voriconazole, such as hyponatremia, which potentially could result in death [3–5]. Voriconazole-related hyponatremia is rare and may lead to drug discontinuation, thus confronting clinicians with an antifungal therapy dilemma. Therapeutic drug monitoring (TDM) comprises the measurement of drug concentrations in biologic fluids to integrate dose, concentration, and pharmacologic effect to understand more precisely the pharmacokinetics and pharmacodynamics of the drug in an individual. General indications for individualization of therapy by means of TDM in specific patient populations include improvement of response to therapy, prevention of drug-related toxicity, and management of drug–drug interactions. TDM has also been suggested for antifungal drug voriconazole, and may contribute to improving therapy in terms of patient outcome, survival, and toxicity [6,7]. In our laboratory, a rapid sensitive and selective HPLC method
n
Corresponding authors: Tel.: +86 0577 15088554595. E-mail addresses: [email protected] (Z.-s. XU), [email protected] (X.-h. ZHANG).
(water:acetonitrile¼ 65:35 as the mobile phases) has been developed and validated for the routine TDM of voriconazole in plasma. We report a case of successful treatment of IPA in a voriconazole-related hyponatremia patient caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).
2. Case A 72-year-old man with a 10 years history of COPD was admitted to our respiratory department because of acute exacerbation. Considering the positive aspergillus cultures of sputum before admission (defined as day 0), he had a higher risk of developing IPA. The patient was immediately treated with intravenous voriconazole (two loading doses of 6 mg/kg, then 4 mg/kg every 12 h) until day+14 and then changed to oral voriconazole tablets at a dose of 200 mg every 12 h. The definite diagnosis of IPA was soon obtained from CT guided percutaneous lung biopsy evidencing Aspergillus fumigatus in culture [8]. On day+26 after commencing voriconazole therapy, the patient showed somnolence and malaise symptoms. Electrolyte levels showed that his sodium level was 104 mmol/L, but that his potassium and creatinine levels were normal. The blood osmolality was 263 mOsm/kg and the patient's urinary sodium was 119 mmol/L. Laboratory data are shown in Table 1. TDM was performed and the voriconazole plasma trough concentration (voriconazole-C0) was high (7.10 μg/ mL). Two days after the discontinuation of voriconazole and infusion of 3% saline, the patient's mental status and hyponatremia improved. Our goal voriconazole-C0 range was 1.0–5.5 μg/mL. The
2211-7539/$ - see front matter & 2013 International Society for Human and Animal Mycology. Published by Elsevier B.V All rights reserved. http://dx.doi.org/10.1016/j.mmcr.2013.06.003
R.-a. Xu et al. / Medical Mycology Case Reports 2 (2013) 134–136
135
Table 1 Laboratory data with voriconazole-associated severe hyponatremia. Full blood cell count White blood cell Lymphocyte Eosinophil absolute Red blood cell Blood chemistry Urea nitrogen Creatinine Uric acid Sodium Potassium Calcium Chloride Albumin Alanine aminotransferase Aspartate aminotransferase Alkaline phosphatase Glucose Osmolality
6.9 109/L 0.5 109/L 0.2 109/L 3.73 1012/L 3.7 mmol/L 49 mmol/L 68 mmol/L 104 mmol/L 3.86 mmol/L 1.83 mmol/L 89 mmol/L 26.8 g/L 42 U/L 117 U/L 559 U/L 6.5 mmol/L 263 mOsm/kg
Urinalysis pH Protein Occult blood Glucose Urine chemistry Sodium Potassium Osmolality Endocrinological results Adrenocorticotropic hormone (0 am) Adrenocorticotropic hormone (8 am) Adrenocorticotropic hormone (4 pm) Cortisol (0 am) Cortisol (8 am) Cortisol (4 pm)
7.0 (+/−) (−) (−) 119 mmol/L 7.55 mmol/L 511 mOsm/kg 56 ng/L 69 ng/L 31 ng/L 93.55 nmol/L 104 nmol/L 126 nmol/L
Fig. 1. Day+52 after voriconazole treatment the lung lesions are no longer visible, and lung CT shows only minor abnormalities compared to before (left: before treatment, right: after treatment).
voriconazole-C0 (0.68 μg/mL), obtained 11 days after a half dose reduction of voriconazole (200 mg/day) on day+39, did not reach the therapeutic range. Since his voriconazole-C0 remained subtherapeutic (0.68 μg/mL), we increased the dose to 300 mg/day after discharge from hospital. On day+52 after the treatment, voriconazole-C0 increased to 1.38 μg/mL, which mostly achieved the target concentration of ≥1.0 μg/mL. The patient remained asymptomatic, and repeat CT findings showed near resolution of lung lesions on following up in our outpatient department (Fig. 1). The CYP2C19 genotype was classified as heterozygous extensive metabolizer (CYP2C19n1/n2).
3. Discussion Approximately 1–2% of overall fatal cases of IPA occur in COPD patients. Antifungal monotherapy using azole voriconazole is recommended as a first-line treatment of IPA [2]. Voriconazole may be associated with many adverse events, including visual disturbance, encephalopathy, rash, hepatic enzyme elevation, and other adverse effects, which may result in drug discontinuation [9]. Among these adverse events, hyponatremia has been rarely reported [3–5] (Table 2). In the present case, hyponatremia was suggested to be a result of the syndrome of inappropriate secretion of antidiuretic
hormone (SIADH) rather than adrenal insufficiency. Adrenal insufficiency might not be suspected as a cause of hyponatremia in our patient, because a maintenance dose of steroid was administered. Therefore, the level of cortisol was slightly low. Moreover, other laboratory data, including lower lymphocyte, eosinophil absolute and calcium levels, and higher blood glucose along with normal urea nitrogen and potassium, could not explain adrenal insufficiency in our patient. Voriconazoleinduced hyponatremia due to salt-losing nephropathy (SLN) has been reported [4], such as cisplatin. However, SLN could not be definitively established because the patient's hyponatremia as a result of compromised re-absorption of sodium at the proximal tubules was not confirmed. Our clinical and laboratory findings suggested that voriconazole-associated severe hyponatremia may be associated with SIADH, the same with previous report [3], rather than SLN (see Table 2). Decreased plasma osmolality, albumin, sodium and chloride levels, increased urinary sodium as well as normal creatinine, urea nitrogen, uric acid levels and thyroid function are in accordance with the criteria for SIADH. The precise mechanism of hyponatremia in this case is unknown for the cause of SIADH itself has not yet been fully elucidated. There is a remarkable interindividual variability of voriconazole blood concentrations, mainly owing to non-linear saturable
136
R.-a. Xu et al. / Medical Mycology Case Reports 2 (2013) 134–136
Table 2 Characteristics of related literatures with voriconazole-associated hyponatremia. Study
Sodium level (mmol/L) Time to hyponatremia (days) Voriconazole trough level (μg/mL) Mechanism of hyponatremia CYP2C19 polymorphism
Isobe et al. [3] 122 Teranishi et al. [4] 113 Kim et al. [5] 114 116 118 This case 104
15 16 10 7 6 26
18 / 9.94 6.12 4.14 7.10
pharmacokinetics, drug–drug interactions, liver disease, patient age, or CYP2C19 genetic polymorphism [10]. This variability makes it particularly difficult to predict exposure to voriconazole and its potential dose-dependent toxicity. Indeed, voriconazoleC0≥1.0 μg/mL have been associated with improved response to therapy and survival [11,12]. Increased adverse events have been associated with voriconazole-C0 4 5.0–6.0 μg/mL [6,13]. As a consequence, TDM may be a useful tool to optimize voriconazole therapy. In our case, voriconazole-C0 was 7.10 μg/mL, which is considered to be in the toxic range. Therefore, voriconazoleassociated hyponatremia may be concentration-dependent. Two days after the discontinuation of voriconazole, this symptomatic progressive hyponatremia got resolved immediately. Instead of discontinuing antifungal therapy, it was decided to reduce the voriconazole dose to 200 mg/day and voriconazole-C0 was subtherapeutic (0.68 μg/mL). Finally, TDM revealed an adequate voriconazole-C00 (1.38 μg/mL) 13 days after dose adjustment to 300 mg/day, suggesting that the dose regimen for this patient was appropriate. So, voriconazole-related hyponatremia suggests the clinical utility of routine TDM of voriconazole reduces drugrelated adverse events and improves treatment outcome in invasive fungal infections. In vitro data show that the hepatic metabolism of voriconazole is mediated primarily by CYP2C19, and to a lesser extent by CYP2C9 and CYP3A4 [14]. It is well known that CYP2C19 exhibits genetic polymorphisms and influences the blood concentration of voriconazole [15]. The frequency of CYP2C19 genetic polymorphism possesses considerable interethnic difference: poor metabolizers of CYP2C19 alleles are more common in Asians (15–20%) than the Caucasian populations (3–5%) [16]. If voriconazole-associated hyponatremia is concentration-dependent, this adverse event may be more common in Asians. In our case, an analysis of genetic polymorphism showed a mutation of cytochrome P450 (CYP2C19n1/n2). Furthermore, the patients did not receive medications known to interfere with voriconazole metabolism. These findings suggest that voriconazoleassociated hyponatremia may be related to CYP2C19 genetic polymorphism. There are similar cases where CYP2C19 genotypes were classified as a heterozygous extensive metabolizer [3,5]. However, there was no homozygous poor metabolizer among all patients. In conclusion, this case suggests that fatally severe hyponatremia can develop after initiating voriconazole antifungal therapy. Furthermore, SIADH and genetic polymorphism of cytochrome P450 may be considered as the cause of voriconazole-related hyponatremia. In addition, this experience confirms the appropriateness of voriconazole dose reduction considered according to voriconazole-C0 instead of therapy interruption . We believe that TDM is useful to determine voriconazole dosage in a voriconazole-related hyponatremia patient. Conflict of interest statement The authors declare no conflict of interest.
SIADH SLN SIADH SIADH SIADH SIADH
CYP2C19n1/n2 / CYP2C19n1/n2 CYP2C19n1/n1 CYP2C19n1/n2 CYP2C19n1/n2
Acknowledgments All authors participated in managing the case and writing the paper. This work was supported by a fund of the Key Academic Subject (clinical Chinese pharmacy) of the Twelfth-Five Year Program of State Administration of Traditional Chinese Medicine, and National Natural Science Foundation of China, No. 81173140.
Appendix A. Supplementary information Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.mmcr.2013.06.003.
References [1] Ader F. Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease: an emerging fungal disease. Current Infectious Disease Reports 2010;12(6):409–16. [2] Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clinical Infectious Diseases 2008;46(3):327–60. [3] Isobe K, Muraoka S, Sugino K, et al. [Case of pulmonary aspergillosis associated with inappropriate antidiuretic hormone syndrome caused by voriconazole therapy]. Nihon Kokyūki Gakkai zasshi 2007;45(6):489–93. [4] Teranishi J, Nagatoya K, Kakita T, et al. Voriconazole-associated salt-losing nephropathy. Clinical and Experimental Nephrology 2010;14(4):377–80. [5] Kim KH, Lee S, Yun NR, et al. Voriconazole-associated severe hyponatremia. Medical Mycology 2012;50(1):103–5. [6] Park WB, Kim NH, Kim KH, et al. The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial. Clinical Infectious Diseases 2012;55(8):1080–7. [7] Dolton MJ, Ray JE, Chen SC, et al. Multicenter study of voriconazole pharmacokinetics and therapeutic drug monitoring. Antimicrobial Agents & Chemotherapy 2012;56(9):4793–9. [8] Sugita C, Makimura K, Uchida K, Yamaguchi H, Nagai APCR. Identification system for the genus Aspergillus and three major pathogenic species: Aspergillus fumigatus, Aspergillus flavus and Aspergillus niger. Medical Mycology 2004;42(5):433–7. [9] Boyd AE, Modi S, Howard SJ, et al. Adverse reactions to voriconazole. Clinical Infectious Diseases 2004;39(8):1241–4. [10] Pasqualotto AC, Xavier MO, Andreolla HF, Linden R. Voriconazole therapeutic drug monitoring: focus on safety. Expert Opinion on Drug Safety 2010;9(1):125–37. [11] Neely M, Rushing T, Kovacs A, Jelliffe R, Hoffman J. Voriconazole pharmacokinetics and pharmacodynamics in children. Clinical Infectious Diseases 2010;50(1):27–36. [12] Pascual A, Calandra T, Bolay S, et al. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clinical Infectious Diseases 2008;46(2):201–11. [13] Bernhard S, Kernland Lang K, Ammann RA, et al. Voriconazole-induced phototoxicity in children. Pediatric Infectious Disease Journal 2012;31(7):769–71. [14] Hyland R, Jones BC, Smith DA. Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole. Drug Metabolism and Disposition 2003;31(5):540–7. [15] Lee S, Kim BH, Nam WS, et al. Effect of CYP2C19 polymorphism on the pharmacokinetics of voriconazole after single and multiple doses in healthy volunteers. Journal of Clinical Pharmacology 2011. [16] Smith J, Andes D. Therapeutic drug monitoring of antifungals: pharmacokinetic and pharmacodynamic considerations. Therapeutic Drug Monitoring 2008;30(2):167–72.
Contents lists available at ScienceDirect
Medical Mycology Case Reports journal homepage: www.elsevier.com/locate/mmcr
Therapeutic drug monitoring in voriconazole-associated hyponatremia Ren-ai Xu a,b, Shuang-li Zheng a, Li-li Xiao a, Xue-ding Cai b, Xi-xi Lai b, Guan-yang Lin b, Lu-feng Hu b, Chun-hong Zhang b, Zhi-sheng Xu a,n, Xiu-hua Zhang b,n a b
The Second Affiliated Hospital of Wenzhou Medical College, Wenzhou 325000, China The First Affiliated Hospital of Wenzhou Medical College, Wenzhou 325000, China
art ic l e i nf o
a b s t r a c t
Article history: Received 18 April 2013 Received in revised form 7 June 2013 Accepted 12 June 2013
Voriconazole is a second generation triazole antifungal agent and the first choice therapy for invasive aspergillosis (IA). Although voriconazole may be associated with many adverse events, hyponatremia has been rarely reported which potentially could result in death. Therapeutic drug monitoring (TDM) and individualization of therapy by measuring voriconazole plasma concentrations improved the efficacy and safety in patients. We report the effect of TDM to adjust voriconazole dosage in a voriconazole-related hyponatremia patient. & 2013 International Society for Human and Animal Mycology. Published by Elsevier B.V All rights reserved.
Keywords: Voriconazole Therapeutic drug monitoring Hyponatremia Invasive pulmonary aspergillosis
1. Introduction Invasive pulmonary aspergillosis (IPA) is a necrotizing pneumonia caused by airborne opportunistic fungi of Aspergillus species [1]. Its frequency increases in patients with Chronic Obstructive Pulmonary Disease (COPD), mainly when steroids are prescribed. Voriconazole is a second generation triazole antifungal agent and the first choice therapy for invasive aspergillosis (IA) [2]. Although voriconazole is generally well tolerated, anecdotal case reports have described unexpected severe adverse events related to voriconazole, such as hyponatremia, which potentially could result in death [3–5]. Voriconazole-related hyponatremia is rare and may lead to drug discontinuation, thus confronting clinicians with an antifungal therapy dilemma. Therapeutic drug monitoring (TDM) comprises the measurement of drug concentrations in biologic fluids to integrate dose, concentration, and pharmacologic effect to understand more precisely the pharmacokinetics and pharmacodynamics of the drug in an individual. General indications for individualization of therapy by means of TDM in specific patient populations include improvement of response to therapy, prevention of drug-related toxicity, and management of drug–drug interactions. TDM has also been suggested for antifungal drug voriconazole, and may contribute to improving therapy in terms of patient outcome, survival, and toxicity [6,7]. In our laboratory, a rapid sensitive and selective HPLC method
n
Corresponding authors: Tel.: +86 0577 15088554595. E-mail addresses: [email protected] (Z.-s. XU), [email protected] (X.-h. ZHANG).
(water:acetonitrile¼ 65:35 as the mobile phases) has been developed and validated for the routine TDM of voriconazole in plasma. We report a case of successful treatment of IPA in a voriconazole-related hyponatremia patient caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).
2. Case A 72-year-old man with a 10 years history of COPD was admitted to our respiratory department because of acute exacerbation. Considering the positive aspergillus cultures of sputum before admission (defined as day 0), he had a higher risk of developing IPA. The patient was immediately treated with intravenous voriconazole (two loading doses of 6 mg/kg, then 4 mg/kg every 12 h) until day+14 and then changed to oral voriconazole tablets at a dose of 200 mg every 12 h. The definite diagnosis of IPA was soon obtained from CT guided percutaneous lung biopsy evidencing Aspergillus fumigatus in culture [8]. On day+26 after commencing voriconazole therapy, the patient showed somnolence and malaise symptoms. Electrolyte levels showed that his sodium level was 104 mmol/L, but that his potassium and creatinine levels were normal. The blood osmolality was 263 mOsm/kg and the patient's urinary sodium was 119 mmol/L. Laboratory data are shown in Table 1. TDM was performed and the voriconazole plasma trough concentration (voriconazole-C0) was high (7.10 μg/ mL). Two days after the discontinuation of voriconazole and infusion of 3% saline, the patient's mental status and hyponatremia improved. Our goal voriconazole-C0 range was 1.0–5.5 μg/mL. The
2211-7539/$ - see front matter & 2013 International Society for Human and Animal Mycology. Published by Elsevier B.V All rights reserved. http://dx.doi.org/10.1016/j.mmcr.2013.06.003
R.-a. Xu et al. / Medical Mycology Case Reports 2 (2013) 134–136
135
Table 1 Laboratory data with voriconazole-associated severe hyponatremia. Full blood cell count White blood cell Lymphocyte Eosinophil absolute Red blood cell Blood chemistry Urea nitrogen Creatinine Uric acid Sodium Potassium Calcium Chloride Albumin Alanine aminotransferase Aspartate aminotransferase Alkaline phosphatase Glucose Osmolality
6.9 109/L 0.5 109/L 0.2 109/L 3.73 1012/L 3.7 mmol/L 49 mmol/L 68 mmol/L 104 mmol/L 3.86 mmol/L 1.83 mmol/L 89 mmol/L 26.8 g/L 42 U/L 117 U/L 559 U/L 6.5 mmol/L 263 mOsm/kg
Urinalysis pH Protein Occult blood Glucose Urine chemistry Sodium Potassium Osmolality Endocrinological results Adrenocorticotropic hormone (0 am) Adrenocorticotropic hormone (8 am) Adrenocorticotropic hormone (4 pm) Cortisol (0 am) Cortisol (8 am) Cortisol (4 pm)
7.0 (+/−) (−) (−) 119 mmol/L 7.55 mmol/L 511 mOsm/kg 56 ng/L 69 ng/L 31 ng/L 93.55 nmol/L 104 nmol/L 126 nmol/L
Fig. 1. Day+52 after voriconazole treatment the lung lesions are no longer visible, and lung CT shows only minor abnormalities compared to before (left: before treatment, right: after treatment).
voriconazole-C0 (0.68 μg/mL), obtained 11 days after a half dose reduction of voriconazole (200 mg/day) on day+39, did not reach the therapeutic range. Since his voriconazole-C0 remained subtherapeutic (0.68 μg/mL), we increased the dose to 300 mg/day after discharge from hospital. On day+52 after the treatment, voriconazole-C0 increased to 1.38 μg/mL, which mostly achieved the target concentration of ≥1.0 μg/mL. The patient remained asymptomatic, and repeat CT findings showed near resolution of lung lesions on following up in our outpatient department (Fig. 1). The CYP2C19 genotype was classified as heterozygous extensive metabolizer (CYP2C19n1/n2).
3. Discussion Approximately 1–2% of overall fatal cases of IPA occur in COPD patients. Antifungal monotherapy using azole voriconazole is recommended as a first-line treatment of IPA [2]. Voriconazole may be associated with many adverse events, including visual disturbance, encephalopathy, rash, hepatic enzyme elevation, and other adverse effects, which may result in drug discontinuation [9]. Among these adverse events, hyponatremia has been rarely reported [3–5] (Table 2). In the present case, hyponatremia was suggested to be a result of the syndrome of inappropriate secretion of antidiuretic
hormone (SIADH) rather than adrenal insufficiency. Adrenal insufficiency might not be suspected as a cause of hyponatremia in our patient, because a maintenance dose of steroid was administered. Therefore, the level of cortisol was slightly low. Moreover, other laboratory data, including lower lymphocyte, eosinophil absolute and calcium levels, and higher blood glucose along with normal urea nitrogen and potassium, could not explain adrenal insufficiency in our patient. Voriconazoleinduced hyponatremia due to salt-losing nephropathy (SLN) has been reported [4], such as cisplatin. However, SLN could not be definitively established because the patient's hyponatremia as a result of compromised re-absorption of sodium at the proximal tubules was not confirmed. Our clinical and laboratory findings suggested that voriconazole-associated severe hyponatremia may be associated with SIADH, the same with previous report [3], rather than SLN (see Table 2). Decreased plasma osmolality, albumin, sodium and chloride levels, increased urinary sodium as well as normal creatinine, urea nitrogen, uric acid levels and thyroid function are in accordance with the criteria for SIADH. The precise mechanism of hyponatremia in this case is unknown for the cause of SIADH itself has not yet been fully elucidated. There is a remarkable interindividual variability of voriconazole blood concentrations, mainly owing to non-linear saturable
136
R.-a. Xu et al. / Medical Mycology Case Reports 2 (2013) 134–136
Table 2 Characteristics of related literatures with voriconazole-associated hyponatremia. Study
Sodium level (mmol/L) Time to hyponatremia (days) Voriconazole trough level (μg/mL) Mechanism of hyponatremia CYP2C19 polymorphism
Isobe et al. [3] 122 Teranishi et al. [4] 113 Kim et al. [5] 114 116 118 This case 104
15 16 10 7 6 26
18 / 9.94 6.12 4.14 7.10
pharmacokinetics, drug–drug interactions, liver disease, patient age, or CYP2C19 genetic polymorphism [10]. This variability makes it particularly difficult to predict exposure to voriconazole and its potential dose-dependent toxicity. Indeed, voriconazoleC0≥1.0 μg/mL have been associated with improved response to therapy and survival [11,12]. Increased adverse events have been associated with voriconazole-C0 4 5.0–6.0 μg/mL [6,13]. As a consequence, TDM may be a useful tool to optimize voriconazole therapy. In our case, voriconazole-C0 was 7.10 μg/mL, which is considered to be in the toxic range. Therefore, voriconazoleassociated hyponatremia may be concentration-dependent. Two days after the discontinuation of voriconazole, this symptomatic progressive hyponatremia got resolved immediately. Instead of discontinuing antifungal therapy, it was decided to reduce the voriconazole dose to 200 mg/day and voriconazole-C0 was subtherapeutic (0.68 μg/mL). Finally, TDM revealed an adequate voriconazole-C00 (1.38 μg/mL) 13 days after dose adjustment to 300 mg/day, suggesting that the dose regimen for this patient was appropriate. So, voriconazole-related hyponatremia suggests the clinical utility of routine TDM of voriconazole reduces drugrelated adverse events and improves treatment outcome in invasive fungal infections. In vitro data show that the hepatic metabolism of voriconazole is mediated primarily by CYP2C19, and to a lesser extent by CYP2C9 and CYP3A4 [14]. It is well known that CYP2C19 exhibits genetic polymorphisms and influences the blood concentration of voriconazole [15]. The frequency of CYP2C19 genetic polymorphism possesses considerable interethnic difference: poor metabolizers of CYP2C19 alleles are more common in Asians (15–20%) than the Caucasian populations (3–5%) [16]. If voriconazole-associated hyponatremia is concentration-dependent, this adverse event may be more common in Asians. In our case, an analysis of genetic polymorphism showed a mutation of cytochrome P450 (CYP2C19n1/n2). Furthermore, the patients did not receive medications known to interfere with voriconazole metabolism. These findings suggest that voriconazoleassociated hyponatremia may be related to CYP2C19 genetic polymorphism. There are similar cases where CYP2C19 genotypes were classified as a heterozygous extensive metabolizer [3,5]. However, there was no homozygous poor metabolizer among all patients. In conclusion, this case suggests that fatally severe hyponatremia can develop after initiating voriconazole antifungal therapy. Furthermore, SIADH and genetic polymorphism of cytochrome P450 may be considered as the cause of voriconazole-related hyponatremia. In addition, this experience confirms the appropriateness of voriconazole dose reduction considered according to voriconazole-C0 instead of therapy interruption . We believe that TDM is useful to determine voriconazole dosage in a voriconazole-related hyponatremia patient. Conflict of interest statement The authors declare no conflict of interest.
SIADH SLN SIADH SIADH SIADH SIADH
CYP2C19n1/n2 / CYP2C19n1/n2 CYP2C19n1/n1 CYP2C19n1/n2 CYP2C19n1/n2
Acknowledgments All authors participated in managing the case and writing the paper. This work was supported by a fund of the Key Academic Subject (clinical Chinese pharmacy) of the Twelfth-Five Year Program of State Administration of Traditional Chinese Medicine, and National Natural Science Foundation of China, No. 81173140.
Appendix A. Supplementary information Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.mmcr.2013.06.003.
References [1] Ader F. Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease: an emerging fungal disease. Current Infectious Disease Reports 2010;12(6):409–16. [2] Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clinical Infectious Diseases 2008;46(3):327–60. [3] Isobe K, Muraoka S, Sugino K, et al. [Case of pulmonary aspergillosis associated with inappropriate antidiuretic hormone syndrome caused by voriconazole therapy]. Nihon Kokyūki Gakkai zasshi 2007;45(6):489–93. [4] Teranishi J, Nagatoya K, Kakita T, et al. Voriconazole-associated salt-losing nephropathy. Clinical and Experimental Nephrology 2010;14(4):377–80. [5] Kim KH, Lee S, Yun NR, et al. Voriconazole-associated severe hyponatremia. Medical Mycology 2012;50(1):103–5. [6] Park WB, Kim NH, Kim KH, et al. The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial. Clinical Infectious Diseases 2012;55(8):1080–7. [7] Dolton MJ, Ray JE, Chen SC, et al. Multicenter study of voriconazole pharmacokinetics and therapeutic drug monitoring. Antimicrobial Agents & Chemotherapy 2012;56(9):4793–9. [8] Sugita C, Makimura K, Uchida K, Yamaguchi H, Nagai APCR. Identification system for the genus Aspergillus and three major pathogenic species: Aspergillus fumigatus, Aspergillus flavus and Aspergillus niger. Medical Mycology 2004;42(5):433–7. [9] Boyd AE, Modi S, Howard SJ, et al. Adverse reactions to voriconazole. Clinical Infectious Diseases 2004;39(8):1241–4. [10] Pasqualotto AC, Xavier MO, Andreolla HF, Linden R. Voriconazole therapeutic drug monitoring: focus on safety. Expert Opinion on Drug Safety 2010;9(1):125–37. [11] Neely M, Rushing T, Kovacs A, Jelliffe R, Hoffman J. Voriconazole pharmacokinetics and pharmacodynamics in children. Clinical Infectious Diseases 2010;50(1):27–36. [12] Pascual A, Calandra T, Bolay S, et al. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clinical Infectious Diseases 2008;46(2):201–11. [13] Bernhard S, Kernland Lang K, Ammann RA, et al. Voriconazole-induced phototoxicity in children. Pediatric Infectious Disease Journal 2012;31(7):769–71. [14] Hyland R, Jones BC, Smith DA. Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole. Drug Metabolism and Disposition 2003;31(5):540–7. [15] Lee S, Kim BH, Nam WS, et al. Effect of CYP2C19 polymorphism on the pharmacokinetics of voriconazole after single and multiple doses in healthy volunteers. Journal of Clinical Pharmacology 2011. [16] Smith J, Andes D. Therapeutic drug monitoring of antifungals: pharmacokinetic and pharmacodynamic considerations. Therapeutic Drug Monitoring 2008;30(2):167–72.
