Download - Farmacogenetics of drug allergy
DRUG ALLERGY What have we learned from immunogenetics?
Natacha Santos, Carmen Botelho, Josefina Cernadas HSJ, Dezembro 2010
Adverse Drug Reactions
“A response to a medicine that is noxiuos and unintended, and which occurs at doses normally used in man”
WHO
Type A Augmented pharmacologic effects
Type B Bizarre effects
Typce C Chronic effects
Type D Delayed effects
Type E End-of-treatment effects
Type F Failure of treatment
objectively reproducible symptoms or signs
initiated by exposure to a defined stimulus at a
dose tolerated by normal persons
Hypersensitivity reactions
Immune-mediated Non Immune-mediated
Drug allergy
Drug allergy
Pichler WJ (ed): Drug Hypersensitivity. Basel, Karger, 2007, pp 168–189
Questions? ¨ Aetiology ¨ Phenotypic-specificity
Drug allergy
Drug
Dose
Route of administration
Co-factors
Genetics
Answers?
Pharmacogenetics
“Is the study of variability
in drug response due to
genetic factors, which are
mainly inherited”
Pharmacoproteomics
Pharmacotranscriptomics
Pharmacogenetics
Pharmacometabolomics
Clinical response
Personalized
Prescription
Pharmacogenetics of Drug Allergy
Pharmacokinetics
Pharmacodynamics
Tissue injury and repair mechanisms
Immune system recognition and responsiveness Immunogenetics
Abacavir
“Within the entire abacavir-exposed cohort, presence of HLA-B*5701, HLA-DR7, and
HLA-DQ3 had a positive predictive value for hypersensitivity of 100%, and a negative
predictive value of 97%.” Lancet. 2002 Mar 2;359(9308):727-32
Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4180-5
“HLA-B*5701 was present in 94.4% of hypersensitive cases compared with 1.7% of
controls. (…) Individuals with abacavir hypersensitivity demonstrated increased
monocyte tumor necrosis factor expression in response to ex vivo abacavir stimulation,
which was abrogated with CD8(+) T cell depletion”
Abacavir
“The cost-effectiveness model demonstrated that depending on the choice of
comparator, routine testing for HLA B*5701 ranged from being a dominant strategy
(less expensive and more beneficial than not testing) to an incremental cost-
effectiveness ratio (versus no testing) of Euro 22,811 per hypersensitivity reaction
avoided.” Pharmacogenetics. 2004 Jun;14(6):335-42
“Detect HLA-B*5701 using allele and group-specific polymerase chain reaction-
sequence-specific primers (PCR-SSP) typing.”
Tissue Antigens. 2005 Jun;65(6):571-4
Screening eliminated immunologically confirmed hypersensitivity reaction (0% in the
prospective-screening group vs. 2.7% in the control group, P<0.001), with a negative
predictive value of 100% and a positive predictive value of 47.9%.
Abacavir
N Engl J Med 2008;358:568-79
Although immunologically confirmed abacavir hypersensitivity reactions are uncommon
in black persons, the 100% sensitivity of HLA-B*5701 as a marker for immunologically
confirmed abacavir hypersensitivity reactions in both US white and black patients
suggests similar implications of the association between HLA-B*5701 positivity and risk
of ABC HSRs in both races. Clin Infect Dis. 2008 Apr 1;46(7):1111-8
Abacavir
FDA ALERT (24/7/2008) “(…) all patients should be screened for the HLA-B*5701 allele before starting or restarting treatment with abacavir or abacavir-containing medications (…)”
EMEA UpDate (24/01/2008) “(…) before initiating treatment with abacavir, screening for carriage of the HLA-B*5701 allele should be performed (…)”
Abacavir
¨ Genetic association with large genetic effect size
¨ Valuable in different ethnical groups
¨ Reproducible. High predictive negative values
¨ Impact on clinical outcome in real-world clinical practise
¨ Cost-effectiveness
Carbamazepine
“There is a strong association in Han Chinese between a genetic marker, the human
leukocyte antigen HLA-B*1502, and Stevens-Johnson syndrome induced by
carbamazepine.” Nature. 2004 Apr 1;428(6982):486
“Preliminary results from a European study (RegiSCAR) of 12 carbamazepine-induced
SJS/TEN cases (nine French and three German). Among these only four had a HLA-
B*1502 allele. Remarkably, these four patients had an Asian ancestry, whereas the
others did not as far as we have ascertained.”
Pharmacogenomics J. 2006 Jul-Aug;6(4):265-8
Carbamazepine
“Confirmed the association of HLA-B*1502 with SJS/TEN. By contrast to CBZ-SJS/TEN,
HLA-B*1502 association was not observed in the maculo-papular eruption or
hypersensitivity syndrome groups.”
Pharmacogenet Genomics. 2006 Apr;16(4):297-306
FDA ALERT (12/12/2007) “(…) Patients with ancestry from areas in which HLA-B*1502 is present should be screened for the HLA-B*1502 allele before starting treatment with carbamazepine(…)”
Allopurinol
”In Han Chinese, the HLA-B*5801 allele was present in all (100%) 51 patients with allopurinol-severe cutaneous
adverse reactions, but only in 20 (15%) of 135 tolerant patients.”
Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):4134-9
“All of the 27 (100%) allopurinol-induced SJS/TEN patients who were examined carried HLA-B*5801 whereas
only seven (12.96%) of the control patients had this allele. The positive predictive value and the negative
predictive value of the HLA-B*5801 allele was 1.52 and 100%, respectively.”
“A strong association between allopurinol-induced severe cutaneous adverse reactions and HLA-B*5801 was
observed in a Han Chinese population with high frequency of this allele, whereas only a moderate association
was observed in populations with low frequency (i.e. European and Japanese).”
Pharmacogenet Genomics. 2009 Sep;19(9):704-9
Late Hypersensitivity reactions
Abacavir DHS HLA-B*5701
Allopurinol SJS/TEN HLA-B*5801
Amoxicilin/clavulanic acid Hepatitis HLA-DRB1*1501
Carbamazepine SJS/TEN HLA-B*1502
HLA-B*5901
HLA-A*0206
MPE HLA-E/HLA-A*3101
Efavirenz Skin rash HLA-DRB1*01
Flucloxacilin Hepatitis HLA-B*5701
Lamotrigine SJS/TEN HLA-B*1502
HLA-B*38
Nevirapine Skin rash HLA-B*3505
HLA-DRB1*01
Hepatitis HLA-Cw8 and HLA-B14(65)
Oxcarbazepine SJS/TEN HLA-B*1502
Phenitoin SJS/TEN HLA-B*1502
Why HLA?
CD8+ T cells in skin biopsies of patients
Elevated tumor necrosis factor-a (TNFa) and interferon-gamma (IFNg)
Positive skin-patch test
Betalactams
“In a chinese population, significant differences of E237G
genotype were observed between patients with positive
benzylpenicillanyl (BPA), phenoxomethylpenicilloyl (PVO) or
ampicilloyl (APO)-IgE and control group. The E237G
variant of the FcepsilonRIbeta gene is involved in the
development of penicillins allergy”
Allergy. 2004 Dec;59(12):1326-32
Betalactams
“Among atopic (french) subjects, we found two distinct
significant associations between immediate beta-
lactam allergy in women and the Ile75Val variant of
IL-4Ralpha gene, and two linked IL-10 promoter gene
polymorphisms, -819C>T and -592 C>A.”
Allergy. 2006 Aug;61(8):921-7
In an Italian population, the combination of the less
frequent allele of the IL13 R130Q polymorphism with
any of the predominant homozygous genotypes of the
three polymorphisms of IL4RA was more significantly
associated with the risk of betalactam allergy than
any polymorphism considered alone
Betalactams
Pharmacogenet Genomics. 2006 Oct;16(10):713-9
NSAIDs
Aspirin-exacerbated respiratory disease
• HLA-DPBI*0301
• LTC4S
• ALOX5
• CYSLT
• PGE2
• TBXA2R
• TBX21
J Clin Pharm Ther. 2008 Oct;33(5):465-72.
NSAIDs
Aspirin-intolerant urticaria
• HLA-DB1*0609
• ALOX5
• FCER1A
• HNMT
J Clin Pharm Ther. 2008 Oct;33(5):465-72.
Drug-allergy pharmacogenetics
¨ Insight of the mechanisms of immune-mediated diseases
¨ Clinical importance - screening
Except for abacavir, carbamazepine and allopurinol, there is no clear evidence that
genetic factors dominate over environmental factors such as concomitant disease
Drug-allergy pharmacogenetics
Enhanced and cheaper genetic technologies
Better patient phenotyping
International database access
Multigenic / whole genome approach
Functional and epigenetic studies
The future?
§ EUDRAGENE
§ Human Genome Project
§ 1000 Genomes Project.
§ REGISCAR
§ Pharmacovigilance Working Party
§ EUDRAVIGILANCE
§ PROTECT
§ International Serious Adverse Event Consortium
Taylor made therapy