title: Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing.
abstract: Phenytoin is a widely used antiepileptic drug with a narrow therapeutic index and large interpatient variability, partly due to genetic variations in the gene encoding cytochrome P450 (CYP)2C9 (CYP2C9). Furthermore, the variant allele HLA-B*15:02, encoding human leukocyte antigen, is associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide recommendations for the use of phenytoin based on CYP2C9 and/or HLA-B genotype (also available on PharmGKB: http://www.pharmgkb.org). The purpose of this guideline is to provide information for the interpretation of HLA-B and/or CYP2C9 genotype tests so that the results can guide dosing and/or use of phenytoin. Detailed guidelines for the use of phenytoin as well as analyses of cost-effectiveness are out of scope. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are periodically updated at http://www.pharmgkb.org.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Caudle
authors.affiliation: Department of Medicinal Chemistry, University of Washington School of Pharmacy, Seattle, Washington, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Rettie
authors.affiliation: Department of Genetics, Stanford University, Palo Alto, California, USA.
authors.forename: M
authors.initials: M
authors.lastname: Whirl-Carrillo
authors.affiliation: Division of Pediatric Neurology, Department of Neurology, Indiana University, Indianapolis, Indiana, USA.
authors.forename: L H
authors.initials: LH
authors.lastname: Smith
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mintzer
authors.affiliation: 1] Laboratory for International Alliance on Genomic Research, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan [2] National Center for Genome Medicine, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan [3] School of Chinese Medicine, China Medical University, Taichung, Taiwan.
authors.forename: M T M
authors.initials: MT
authors.lastname: Lee
authors.affiliation: Department of Genetics, Stanford University, Palo Alto, California, USA.
authors.forename: T E
authors.initials: TE
authors.lastname: Klein
authors.affiliation: 1] Division of Clinical Pharmacology, Department of Medicines, Indiana University School of Medicine and Pharmacology/Toxicology, Indianapolis, Indiana, USA [2] Department of Veterans Affairs, RLR VA Medical Center, Indianapolis, Indiana, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Callaghan
mesh_terms: D000927:Anticonvulsants / Q000008:administration & dosage*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D005838:Genotype; D015235:HLA-B Antigens / Q000235:genetics*; D006801:Humans; D010597:Pharmacogenetics; D010641:Phenotype; D010672:Phenytoin / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000927:Anticonvulsants; D015235:HLA-B Antigens; D010672:Phenytoin; D065729:Cytochrome P-450 CYP2C9
references.citation: Pharmacogenetics. 2002 Apr;12(3):251-63
references.pmid: 11927841
references.citation: Seizure. 2011 Mar;20(2):160-2
references.pmid: 21169036
references.citation: Epilepsia. 2013 Jul;54(7):1307-14
references.pmid: 23692434
references.citation: J Eur Acad Dermatol Venereol. 2009 Jun;23(6):702-3
references.pmid: 18785891
references.citation: J Pharmacol Exp Ther. 2004 Mar;308(3):965-74
references.pmid: 14634042
references.citation: Pharmacogenomics J. 2013 Aug;13(4):359-61
references.pmid: 22641027
references.citation: Neurol India. 2007 Oct-Dec;55(4):408-9
references.pmid: 18040121
references.citation: Ther Drug Monit. 1994 Apr;16(2):145-50
references.pmid: 8009561
references.citation: Eur J Biochem. 1985 Sep 2;151(2):345-50
references.pmid: 2411555
references.citation: Neurology. 2012 Sep 18;79(12):1259-67
references.pmid: 22955130
references.citation: Epilepsia. 2009 Jul;50(7):1837-8
references.pmid: 20831525
references.citation: Clin Pharmacol Ther. 2012 Apr;91(4):734-8
references.pmid: 22378157
references.citation: Pharmacogenomics J. 2001;1(3):204-10
references.pmid: 11908757
references.citation: Clin Pharmacol Ther. 2001 Oct;70(4):391-4
references.pmid: 11673755
references.citation: Br J Clin Pharmacol. 2003 Dec;56 Suppl 1:37-44
references.pmid: 14616412
references.citation: Pharmacogenetics. 2001 Jun;11(4):287-91
references.pmid: 11434505
references.citation: Pharmacogenet Genomics. 2012 Jun;22(6):466-70
references.pmid: 22569204
references.citation: Epilepsia. 2008 Dec;49(12):2087-91
references.pmid: 18637831
references.citation: J Clin Pharmacol. 2009 Dec;49(12):1483-7
references.pmid: 19617466
references.citation: Clin Pharmacol Ther. 2012 Dec;92(6):757-65
references.pmid: 23132554
references.citation: Ther Drug Monit. 2004 Oct;26(5):534-40
references.pmid: 15385837
references.citation: Clin Pharmacol Ther. 2013 Feb;93(2):153-8
references.pmid: 23232549
references.citation: Pharmacogenomics. 2012 Sep;13(12):1339-49
references.pmid: 22966884
references.citation: Clin Pharmacol Ther. 2012 Oct;92(4):414-7
references.pmid: 22992668
references.citation: Clin Pharmacol Ther. 2011 Oct;90(4):625-9
references.pmid: 21900891
references.citation: Br J Clin Pharmacol. 1999 Sep;48(3):409-15
references.pmid: 10510154
references.citation: Neurology. 1979 Feb;29(2):175-8
references.pmid: 571061
references.citation: Pharmacogenomics. 2010 Mar;11(3):349-56
references.pmid: 20235791
references.citation: Kaohsiung J Med Sci. 2009 Feb;25(2):82-6
references.pmid: 19321411
references.citation: Seizure. 2011 Jun;20(5):431-2
references.pmid: 21334226
references.citation: Epilepsy Res. 1999 Jul;35(3):253-5
references.pmid: 10413320
references.citation: Clin Pharmacol Ther. 2013 Sep;94(3):324-8
references.pmid: 23695185
references.citation: Seizure. 2013 Apr;22(3):194-7
references.pmid: 23298603
references.citation: Aust N Z J Med. 1975 Oct;5(5):462-6
references.pmid: 1061551
references.citation: Ann Neurol. 2009 Apr;65(4):448-56
references.pmid: 19296463