Risk assessment for phenytoin-induced adverse drug reactions

a risk assessment and drug technology, applied in the field of risk assessment of adverse drug reactions in response to phenytoin, can solve the problems of delayed clearance and severe cutaneous adverse reactions of phenytoin

Inactive Publication Date: 2015-08-13
CHANG GUNG MEDICAL FOUND CHANG GUNG MEMORIAL HOSPITAL AT KEELUNG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006]The present invention provides a method of predicting the risk of a patient for developing phenytoin-related adverse drug reactions, particularly the severe cutaneous adverse reactions (SCAR), including SJS, TEN and DRESS. This invention provides kits which test the presence of specific alleles of CYP2C and HLA genes, can be used to avoid the occurrence of phenytoin-induced SJS / TEN / DRESS.

Problems solved by technology

Patients with these variants showed delayed clearance of the drugs, and developed phenytoin-related severe cutaneous adverse reactions.

Method used

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  • Risk assessment for phenytoin-induced adverse drug reactions
  • Risk assessment for phenytoin-induced adverse drug reactions
  • Risk assessment for phenytoin-induced adverse drug reactions

Examples

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example 1

Variants on CYP2C Genes and Phenytoin-Related SCAR

[0050]In the cohort of 168 individuals with phenytoin-related ADRs, 90 cases were diagnosed to have S] S / TEN / DRESS, and 78 individuals had milder cutaneous adverse drug reactions (erythema multiform, maculopapular rash or fixed drug eruption). The control group consisted of 198 subjects. By using genome wide association study (Affymetrix 6.0) of 58 phenytoin-induced SCARs (including SJS, TEN, and DRESS) and 198 population controls, it is found that the most significant SNPs were in chromosome 10 (see FIG. 1) of the CYP2C region, such as rs17110192, rs7896133 on CYP2C18; rs17110321, rs9332093, rs9332245 on CYP2C9; rs3758581, rs2860905, rs4086116 on CYP2C19 and rs7899038, rs1592037, rs1934952, rs11572139, rs6583967 on CYP2C8 (see Table 1). The other SNPs which located nearby CYP2C loci, such as rs2274222, rs11188183, rs7921561, rs10882544, rs7084271, rs644437, rs12769577, rs617848, rs10882551, rs585381, rs648638, rs664093, rs12262878, ...

example 2

HLA Alleles and Phenytoin-Related SCAR

[0056]The HLA susceptibility of phenytoin-related cutaneous adverse reactions was analyzed due to the presence of immunological characteristics in the disease. Specific oligonucleotide primers and probes were used to identify the HLA-A, HLA-B and HLA-DRB1 genotype of phenytoin-ADRs patients and tolerant controls. The results indicated that HLA-A*0207, HLA-A*2402, HLA-B*1301, HLA-B*1502, HLA-B*4001, HLA-B*4609, HLA-B*5101, HLA-DRB1*1001 or HLA-DRB1*1502 were significantly associated with phenytoin-induced ADRs (SJS / TEN, DRESS, or MPE) (see Table 4 to 6). The data shows that HLA-B*1301 allele significantly increased frequencies among patients with phenytoin-ADRs compared to the tolerant controls. There were 15 SJS / TEN patients (28.3%) and 12 DRESS patients (46.2%) carried HLA-B*1301, while only 14 tolerant patients (11.9%) carried this genotype (SJS / TEN vs. tolerant controls: P=0.001, OR=3.8 (1.7-8.5); DRESS vs. tolerant controls: P=2×10−4, OR=6.4...

example 3

Combination of CYP2C and HLA Alleles for Predicting Phenytoin-SCAR

[0059]We designed kits which consisted reagents and oligonucleotide primers and probes for detecting the presence of the risk alleles selected from a panel, comprising rs1057910 (CYP2C9*3), rs3758581, and HLA-B*1502, HLA-B*1301, and HLA-B*5101. The detection of both CYP2C alleles and HLA alleles further improved the sensitivity of test for phenytoin-related SCAR. For example, the sensitivity of a CYP2C genetic test which detects the presence of either rs1057910 or rs3758581, could be improved with the inclusion of HLA-B*15:02 allele in the testing panel, in which the sensitivity will be 55.93%, and the specificity of 90.77%, positive predictive value (PPV) of 77.33%, and negative predictive value (NPV) of 81.94% for predicting phenytoin-SJS / TEN. Furthermore, adding HLA-B*1301 and HLA-B*5101 to CYP2C (rs1057910 / rs3758581) genetic screening improved the sensitivity to 67.27% for all types of phenytoin-SCAR, including SJ...

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Abstract

A method of predicting the risk of a patient for developing phenytoin-induced adverse drug reactions (ADRs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug reactions with eosinophilia and systemic symptoms (DRESS) is disclosed. Genetic polymorphisms of CYP2C genes (including rs1057910 (CYP2C9*3) and rs3758581 on CYP2C19), and HLA alleles (including HLA-B*1502, HLA-B*1301, and HLA-B*5101) can predict adverse reactions caused by phenytoin or fosphenytoin. Accordingly, the present invention provides a kit to assess the risk of a patient for developing adverse reactions in response to phenytoin-related drugs, which comprises the determination of the presence of a specific allele selected from the group consisting of rs1057910 (CYP2C9*3), rs3758581 on CYP2C19, HLA-B*1502, HLA-B*1301, and HLA-B*5101, wherein the presence of at least one allele is indicative of a risk for the adverse drug reactions.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation-in-part of U.S. application Ser. No. 13 / 323,515, filed Dec. 12, 2011, entitled “RISK ASSESSMENT FOR PHENYTOIN-INDUCED ADVERSE DRUG REACTIONS”. The entire teachings of the above application are incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention is related to a method for predicting the risk of a patient for adverse drug reactions, and more particularly to a risk assessment for developing adverse drug reactions in response to phenytoin.BACKGROUND OF THE INVENTION[0003]Adverse drug reactions (abbreviated ADRs) are expressions that describe harm associated with the use of given medication at a normal dosage. Drug hypersensitivity is a common adverse event during medical treatments and contributes to about 20% of reported ADRs. These hypersensitivity reactions may present from mild skin rash (MPE) to life-threatening drug reaction with eosinophilia and systemic symptoms (DRESS)...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12Q1/68
CPCC12Q1/6881C12Q2600/106C12Q2600/172C12Q2600/16C12Q1/6883C12Q2600/118C12Q2600/156
Inventor CHUNG, WEN-HUNGHUNG, SHUEN-IU
Owner CHANG GUNG MEDICAL FOUND CHANG GUNG MEMORIAL HOSPITAL AT KEELUNG
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