Brain & Development xxx (2015) xxx–xxx www.elsevier.com/locate/braindev
Case Report
Phenytoin toxicity in two-month-old Thai infant with CYP2C9 gene polymorphism – A case report Montida Veeravigrom a,b,⇑, Vorapol Jaroonvanichkul c, Wiracha Netbaramee a,b, Pichaya Phaisarn a,b, Thanita Uyathanarat a,b b
a Division of Neurology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Thailand Division of Neurology, Department of Pediatrics, King Chulalongkorn Memorial Hospital/Thai Red Cross Society, Thailand c Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Thailand
Received 16 September 2014; received in revised form 9 April 2015; accepted 3 May 2015
Abstract Phenytoin is one of the most well established and most effective antiepileptic medications for the treatment of focal seizures. In our clinical practice, it has proven difficult to maintain therapeutic phenytoin levels in infants less than three months of age. Incidence of phenytoin toxicity in infants is very rare. The cytochrome P450 super family plays an important role in phenytoin metabolism, especially CYP2C9 and CYP2C19. In this case report, we profiled a two-month-old Thai infant who developed phenytoin toxicity resulting from CYP2C9 gene polymorphism. Ó 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Phenytoin toxicity; Infant; CYP2C9 gene polymorphism
1. Introduction
2. Case report
Phenytoin is one of the most established, widely prescribed, and most effective antiepileptic medications for the treatment of focal seizures. In our clinical practice, it has been difficult to maintain therapeutic phenytoin levels in infants less than three months of age. Phenytoin toxicity in infants is very rare [1]. In this case report, we profiled a case of phenytoin toxicity in a two-month-old Thai infant resulting from CYP2C9 gene polymorphism. This case report was approved by the Institutional Review Board, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
The patient was a two-month-old male infant with VACTERL association (vertebral anomalies, anal atresia, cardiac defects, tracheo-esophageal fistula, renal and radial anomalies, and limb defects) who was born with imperforated anus and rectovesical fistula post-transverse colostomy. His other anomalies included left single kidney with moderate hydronephrosis, hydroureter, patent ductus arteriosus (PDA), subaortic ventricular septal defect (VSD), patent foramen ovale, and hemivertebrae with scoliosis T5-9. He was admitted to the hospital with a diagnosis of acute diarrhea with septicemia. A lumbar puncture was performed, which revealed a normal CSF profile. The patient had been receiving Ceftriaxone and subsequently changed to Meropenem. One week later, he experienced a focal tonic-clonic seizure at the left arm and leg that
⇑ Corresponding author at: Division of Neurology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand. Tel.: +66 92 263 9773; fax: +66 2 256 5275. E-mail address: [email protected] (M. Veeravigrom).
http://dx.doi.org/10.1016/j.braindev.2015.05.001 0387-7604/Ó 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Veeravigrom M et al. Phenytoin toxicity in two-month-old Thai infant with CYP2C9 gene polymorphism – A case report. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.05.001
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M. Veeravigrom et al. / Brain & Development xxx (2015) xxx–xxx
lasted for 2 min. He received a loading dose of intravenous (IV) phenytoin (DilantinÒ, Pfizer, New York City, NY, USA) 20 mg/kg with IV maintenance dose of 7 mg/kg/day. Four days following the introduction of IV phenytoin, the patient experienced two successive left-sided focal seizures. Blood phenytoin level was evaluated and intravenous phenytoin 10 mg/kg was given. Maintenance dose was increased to 10 mg/kg/day. After the second loading dose of phenytoin was given, no further clinical seizures were observed. The patient then became lethargic. He awoke with only tactile stimulation or very loud sounds. When we woke him up, he opened his eyes and moved his extremities. He remained awake for 10–15 min each time and then fell back to sleep. He drank very little milk and cried with moderate tactile response or pain. His pediatric Glasglow coma scale during those periods was E3M5V3. He did not have fever or other signs of infection. A septic work-up was performed and the results were negative. Phenytoin toxicity was suspected. The trough phenytoin level before second loading dose was 50.22 lg/ml, with a repeated trough phenytoin level 48 h after second loading dose at 53.63 lg/ml. Phenytoin was then discontinued. Patient lethargy symptoms showed continuous improvement to E4M6V5 within 4 days. Seven days after discontinuation, phenytoin level was 0.9 lg/ml. (Fig. 1) As a result of phenytoin toxicity onset after the administration of standard age-group-specific dose (this patient age group normally requires a higher dose to maintain therapeutic level), pharmacogenetic testing (CYP2C9, CYP2C19) was performed using
exon-specific polymerase chain reaction (PCR) amplification, followed by simple probe chemistry and melting curve analysis with LightMixÒ Kit human (TIB MOLBIOL GmbH, Berlin, Germany) for the detection of CYP2C9*2 CYP2C9*3, CYP2C19*2, and * CYP2C19 3. Test results showed that the patient had CYP2C9*1/*3 (slow metabolizer polymorphism) and CYP2C19*1/*1 (normal metabolizer polymorphism). 3. Discussion Phenytoin is one of the antiepileptic medications that pediatricians and pediatric neurologists prescribe for infants less than 3 months of age. Phenytoin has a narrow therapeutic range, with toxicity occasionally observed in children and adults. Phenytoin toxicity, however, is very rare in neonates. Given the incidence of phenytoin toxicity being very rare in this age group, physicians have routinely increased the phenytoin dosage to stop and prevent further seizures without monitoring the patient’s phenytoin level. Phenytoin is metabolized by an enzyme from the cytochrome P450 super family; an activity dependent on the genetic polymorphism of CYP2C9 and CYP2C19 [2]. Fifty-eight alleles relating to CYP2C9 have been identified. CYP2C9*1 is classified as a wild-type (WT) allele. CYP2C9*3 is one of the mutant alleles that is characterized by 3–5% enzyme activity, as compared with wild-type alleles [3]. Our patient tested positive for heterozygous CYP2C9*3, which explained the patient’s phenytoin toxicity. Given variation in the
Fig. 1. Timeline of patient phenytoin plasma concentration levels. Trough phenytoin level at day 4 after first loading dose (20 mg/kg) and maintenance dose (7 mg/kg/day) was 50.22 lg/ml. Repeated trough phenytoin level at 48 h after second loading dose (10 mg/kg) was 53.63 lg/ml. Phenytoin was then discontinued. Seven days after discontinuation, phenytoin level decreased to 0.9 lg/ml.
Please cite this article in press as: Veeravigrom M et al. Phenytoin toxicity in two-month-old Thai infant with CYP2C9 gene polymorphism – A case report. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.05.001
M. Veeravigrom et al. / Brain & Development xxx (2015) xxx–xxx
metabolism of phenytoin from patient to patient, pharmacogenetic testing improves our ability to understand individual patient rates of phenytoin metabolism. There have been several reports of phenytoin toxicity in newborns and infants [4]. In a comprehensive review of the literature and to the best of our knowledge, this case is the first to report phenytoin toxicity in an infant due to CYP2C9 polymorphism.
Acknowledgements The authors gratefully acknowledge the Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Mahidol University, Bangkok, Thailand and Thawinee
Jantararoungtong information.
for
3
pharmacogenetic
testing
References [1] Cheng A, Banwell B, Levin S, Seabrook JA, Freeman D, Rieder M. Oral dosing requirements for phenytoin in the first three months of life. J Popul Ther Clin Pharmacol 2010;17:e256–61. [2] Allabi AC, Gala JL, Horsmans Y. CYP2C9, CYP2C19, ABCB1 (MDR1) genetic polymorphisms and phenytoin metabolism in a Black Beninese population. Pharmacogenet Genomics 2005;15:779–86. [3] Anderson GD. Pharmacogenetics and enzyme induction/inhibition properties of antiepileptic drugs. Neurology 2004;63:S3–8. [4] Lowry JA, Vandover JC, DeGreeff J, Scalzo AJ. Unusual presentation of iatrogenic phenytoin toxicity in a newborn. J Med Toxicol 2005;1:26–9.
Please cite this article in press as: Veeravigrom M et al. Phenytoin toxicity in two-month-old Thai infant with CYP2C9 gene polymorphism – A case report. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.05.001
Case Report
Phenytoin toxicity in two-month-old Thai infant with CYP2C9 gene polymorphism – A case report Montida Veeravigrom a,b,⇑, Vorapol Jaroonvanichkul c, Wiracha Netbaramee a,b, Pichaya Phaisarn a,b, Thanita Uyathanarat a,b b
a Division of Neurology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Thailand Division of Neurology, Department of Pediatrics, King Chulalongkorn Memorial Hospital/Thai Red Cross Society, Thailand c Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Thailand
Received 16 September 2014; received in revised form 9 April 2015; accepted 3 May 2015
Abstract Phenytoin is one of the most well established and most effective antiepileptic medications for the treatment of focal seizures. In our clinical practice, it has proven difficult to maintain therapeutic phenytoin levels in infants less than three months of age. Incidence of phenytoin toxicity in infants is very rare. The cytochrome P450 super family plays an important role in phenytoin metabolism, especially CYP2C9 and CYP2C19. In this case report, we profiled a two-month-old Thai infant who developed phenytoin toxicity resulting from CYP2C9 gene polymorphism. Ó 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Phenytoin toxicity; Infant; CYP2C9 gene polymorphism
1. Introduction
2. Case report
Phenytoin is one of the most established, widely prescribed, and most effective antiepileptic medications for the treatment of focal seizures. In our clinical practice, it has been difficult to maintain therapeutic phenytoin levels in infants less than three months of age. Phenytoin toxicity in infants is very rare [1]. In this case report, we profiled a case of phenytoin toxicity in a two-month-old Thai infant resulting from CYP2C9 gene polymorphism. This case report was approved by the Institutional Review Board, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
The patient was a two-month-old male infant with VACTERL association (vertebral anomalies, anal atresia, cardiac defects, tracheo-esophageal fistula, renal and radial anomalies, and limb defects) who was born with imperforated anus and rectovesical fistula post-transverse colostomy. His other anomalies included left single kidney with moderate hydronephrosis, hydroureter, patent ductus arteriosus (PDA), subaortic ventricular septal defect (VSD), patent foramen ovale, and hemivertebrae with scoliosis T5-9. He was admitted to the hospital with a diagnosis of acute diarrhea with septicemia. A lumbar puncture was performed, which revealed a normal CSF profile. The patient had been receiving Ceftriaxone and subsequently changed to Meropenem. One week later, he experienced a focal tonic-clonic seizure at the left arm and leg that
⇑ Corresponding author at: Division of Neurology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand. Tel.: +66 92 263 9773; fax: +66 2 256 5275. E-mail address: [email protected] (M. Veeravigrom).
http://dx.doi.org/10.1016/j.braindev.2015.05.001 0387-7604/Ó 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Veeravigrom M et al. Phenytoin toxicity in two-month-old Thai infant with CYP2C9 gene polymorphism – A case report. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.05.001
2
M. Veeravigrom et al. / Brain & Development xxx (2015) xxx–xxx
lasted for 2 min. He received a loading dose of intravenous (IV) phenytoin (DilantinÒ, Pfizer, New York City, NY, USA) 20 mg/kg with IV maintenance dose of 7 mg/kg/day. Four days following the introduction of IV phenytoin, the patient experienced two successive left-sided focal seizures. Blood phenytoin level was evaluated and intravenous phenytoin 10 mg/kg was given. Maintenance dose was increased to 10 mg/kg/day. After the second loading dose of phenytoin was given, no further clinical seizures were observed. The patient then became lethargic. He awoke with only tactile stimulation or very loud sounds. When we woke him up, he opened his eyes and moved his extremities. He remained awake for 10–15 min each time and then fell back to sleep. He drank very little milk and cried with moderate tactile response or pain. His pediatric Glasglow coma scale during those periods was E3M5V3. He did not have fever or other signs of infection. A septic work-up was performed and the results were negative. Phenytoin toxicity was suspected. The trough phenytoin level before second loading dose was 50.22 lg/ml, with a repeated trough phenytoin level 48 h after second loading dose at 53.63 lg/ml. Phenytoin was then discontinued. Patient lethargy symptoms showed continuous improvement to E4M6V5 within 4 days. Seven days after discontinuation, phenytoin level was 0.9 lg/ml. (Fig. 1) As a result of phenytoin toxicity onset after the administration of standard age-group-specific dose (this patient age group normally requires a higher dose to maintain therapeutic level), pharmacogenetic testing (CYP2C9, CYP2C19) was performed using
exon-specific polymerase chain reaction (PCR) amplification, followed by simple probe chemistry and melting curve analysis with LightMixÒ Kit human (TIB MOLBIOL GmbH, Berlin, Germany) for the detection of CYP2C9*2 CYP2C9*3, CYP2C19*2, and * CYP2C19 3. Test results showed that the patient had CYP2C9*1/*3 (slow metabolizer polymorphism) and CYP2C19*1/*1 (normal metabolizer polymorphism). 3. Discussion Phenytoin is one of the antiepileptic medications that pediatricians and pediatric neurologists prescribe for infants less than 3 months of age. Phenytoin has a narrow therapeutic range, with toxicity occasionally observed in children and adults. Phenytoin toxicity, however, is very rare in neonates. Given the incidence of phenytoin toxicity being very rare in this age group, physicians have routinely increased the phenytoin dosage to stop and prevent further seizures without monitoring the patient’s phenytoin level. Phenytoin is metabolized by an enzyme from the cytochrome P450 super family; an activity dependent on the genetic polymorphism of CYP2C9 and CYP2C19 [2]. Fifty-eight alleles relating to CYP2C9 have been identified. CYP2C9*1 is classified as a wild-type (WT) allele. CYP2C9*3 is one of the mutant alleles that is characterized by 3–5% enzyme activity, as compared with wild-type alleles [3]. Our patient tested positive for heterozygous CYP2C9*3, which explained the patient’s phenytoin toxicity. Given variation in the
Fig. 1. Timeline of patient phenytoin plasma concentration levels. Trough phenytoin level at day 4 after first loading dose (20 mg/kg) and maintenance dose (7 mg/kg/day) was 50.22 lg/ml. Repeated trough phenytoin level at 48 h after second loading dose (10 mg/kg) was 53.63 lg/ml. Phenytoin was then discontinued. Seven days after discontinuation, phenytoin level decreased to 0.9 lg/ml.
Please cite this article in press as: Veeravigrom M et al. Phenytoin toxicity in two-month-old Thai infant with CYP2C9 gene polymorphism – A case report. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.05.001
M. Veeravigrom et al. / Brain & Development xxx (2015) xxx–xxx
metabolism of phenytoin from patient to patient, pharmacogenetic testing improves our ability to understand individual patient rates of phenytoin metabolism. There have been several reports of phenytoin toxicity in newborns and infants [4]. In a comprehensive review of the literature and to the best of our knowledge, this case is the first to report phenytoin toxicity in an infant due to CYP2C9 polymorphism.
Acknowledgements The authors gratefully acknowledge the Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Mahidol University, Bangkok, Thailand and Thawinee
Jantararoungtong information.
for
3
pharmacogenetic
testing
References [1] Cheng A, Banwell B, Levin S, Seabrook JA, Freeman D, Rieder M. Oral dosing requirements for phenytoin in the first three months of life. J Popul Ther Clin Pharmacol 2010;17:e256–61. [2] Allabi AC, Gala JL, Horsmans Y. CYP2C9, CYP2C19, ABCB1 (MDR1) genetic polymorphisms and phenytoin metabolism in a Black Beninese population. Pharmacogenet Genomics 2005;15:779–86. [3] Anderson GD. Pharmacogenetics and enzyme induction/inhibition properties of antiepileptic drugs. Neurology 2004;63:S3–8. [4] Lowry JA, Vandover JC, DeGreeff J, Scalzo AJ. Unusual presentation of iatrogenic phenytoin toxicity in a newborn. J Med Toxicol 2005;1:26–9.
Please cite this article in press as: Veeravigrom M et al. Phenytoin toxicity in two-month-old Thai infant with CYP2C9 gene polymorphism – A case report. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.05.001
