PED3014 L9 Genetic susceptibility to adverse drug reactions

Intrinsic or type A adverse drug reactions

• predictable on the basis of drug concentrations

• e.g. bleeding due to warfarin dose

idiosyncratic or type B adverse drug reactions

• not predictable based on known drug pharmacology

• not usually related to dose

• rare but often very serious

  • e.g. liver toxicity due to a range of different drugs (at recommended dose)

  • cardiotoxicity

idiosynchratic adverse drug reactions are:

• not predictable on basis of known pharmacology

• usually rare

• normally not detected before drug is licensed

• relatively large number of widely used drugs linked

Idiosyncratic ADRs with pharmacogenetic findings on susceptibility

• hypersensitivity/skin rash -abacavir

• hepatotoxicity -flucloxacillin

• myopathy -statins

• cardiotoxicity

HLA genes - a common thread in serious adverse drug reaction

• HLA class I genes expressed on most cells

• HLA class II genes expressed on APCs

• HLA proteins normally present peptide antigens to T cells

  • may inappropriately present drug-peptide complexes

Abacavir hypersensitivity

widely used antiretroviral reverse-transcriptase inhibitor

• T cells from HLA-B positive donors only proliferate and differentiate into vitro when stimulated with abacavir, giving CD8-positive cytotoxic T cells

• activated abacavir binds directly to B*57:01 gene product and this leads to inappropriate recognition of self peptides

stevens johnson syndrome induced by drug exposure

• carbamazepine

• allopurinol

Flucloxacillin

• beta lactamase resistant penicillin with isolxazolyl ring

• cause of liver injury

HLA and related gene associations with DILI-underlying mechanism

• inappropriate T-cell response

• mechanism for HLA protein interaction with drug appears different to that of abacavir

• Specific HLA protein interacts with drug complex to peptide inappropriately and presents this to T cells causing reaction

• local cellular damage

statin-induced myopathy

- Ranges from mild myalgia to very rare but life-threatening

rhabdomyolysis

• Genome-wide association study (GWAS) shows important role

in myopathy relating to simvastatin for SLCO1B1 variant

associated with decreased hepatic uptake

• SLCO1B1 encodes main inward hepatic statin transporter as discussed

in Lecture 7

• Higher plasma level of drug in those with decreased activity *5

variant

• May result in increased uptake into muscle tissue

GWAS studies on drug-induced long QI and Torsades de pointes

At least two now published but no genome-wide significance

seen

• Likely to be due to sample sizes (200 to 300) being too small

• General conclusion is that common genetic variants are not

important predictors for drug-induced cardiotoxicity

• More difficult to screen for rare variants but possible by exome

sequencing