Pharmacogenomics

Clara Gorodezky, Susie Leffell

Introduction:

Pharmacogenomic information is contained in about 10% of labels for drugs by the U.S. Food and Drug Administration (FDA) because of the role they play in drug-host interactions. Immunogenetic factors may contribute to the responses evoked by certain drugs, as in the case of two established host-drug interactions, carbamazepine and abacivir.  Serious adverse reactions to these drugs in association with certain HLA alleles have been confirmed in some ethnic groups, but have not been investigated in other populations.  It is also likely that additional associations may be established for other drugs with increasing awareness of possible immunogenetic predisposition.  

Aim:

The aim of this study is to establish an ongoing registry for compilation of data on the incidence of the association of HLA alleles and/or other immunogenetic factors with adverse drug reactions in various populations.

Goals:

1. The primary goal will be an MHC specific loci retrospective analysis of the drug-host interactions for carbamazepine and abacavir in non-white populations. Carbamazepine evokes serious dermatologic reactions in patients who are carriers of the B*15:02 allele Therefore, the FDA has recommended that prior to initiating carbamazepine therapy in neurologic patients, HLA typing should be performed in patients of ethnic populations in which this allele exists.
   
   

   Abacavir produces hypersensitivity reactions/lactic acidosis and severe hepatomegaly in immunosuppressed patients that are positive for B*57:01 allele. Patients who carry this allele are at a very high risk for experiencing hypersensitivity reactions to abacavir. Therefore, FDA has also recommended strongly that prior to the drug administration in immunosuppressed patients, such as those with AIDS, should be screened for the presence of B*57:01. Data currently exist for White and Black patients, but there is little or no data available for other ethnic groups.
   

2. A secondary goal will be to begin collecting data on other potential pharmacogenetic associations.  Two potential drugs for investigation will include busulfan and desatinib, both of which have reported adverse effects in treatment of Philadelphia chromosome negative CML and Philadelphia chromosome positive ALL, respectively.

General Guidelines for Participation:

• For carbamazepine and abacavir, the studies may be retrospective in either neurologic patients or immunosuppressed patients who had received these respective drugs.  Different populations must be included, because it has been reported that some groups may have protective alleles to carbamazepine, such as Australian and British Caucasians and Orientals, in contrast to Chinese who have severe adverse reactions if they are B*15:02+.  In the case of B*57:01, although Whites and Blacks have been studied, very few other reports are found in the literature.
  
  

  The interested laboratories should have collaborative agreements with clinical specialists to include at least 50 patients with adverse reactions and 50 patients with no reaction to the drug.

• It will be the responsibility of each participating laboratory to obtain appropriate institutional review board approvals for their participation. All data submitted will be de-identified with assigned workshop code numbers.

• For submission of data on possible associations with busulfan and desatinib, smaller case numbers are acceptable, but should also include appropriately matched controls without adverse reactions. Criteria should include ethnicity, underlying disease, and age.

• The inclusion and exclusion criteria for adverse drug reactions will be given by the Chairs of this Component in accordance with input from clinical specialists.

• The ethnic groups must be well selected according to anthropologic and population criteria. Patients and controls should be derived from the same ethnic group. Forms for obtaining demographic information on the enrolled subjects will be provided by the chairs.

• HLA high resolution typing of Class I alleles and Class II alleles must be done in every case.

• Participants most participate in QC by re-typing in central labs of 10 samples.

• Appropriate institution review board approval and informed consent must be obtained.

• Assistance with allele level typing will be provided on limited basis from central labs.

• The data must be sent to the component to do a central statistical analysis. Forms for electronic data entry will be provided and should be emailed to the chairs upon completion.

Contact:
Email: clarag [at] servidor [dot] unam [dot] mx or msleffel [at] jhmi [dot] edu

Download a PDF of the ASHI 2010 Presentation - download PDF file.

Download a PDF of the EFI 2011 Presentation - download PDF file.

Download a PDF of the ASHI 2011 Presentation - download PDF file.

Nov 11, 2011 Posted by Admin