Adverse Drug Reactions: Intrinsic and Idiosyncratic

Adverse Reactions

• Intrinsic (Type A) reactions are predictable based on drug concentrations and are more common than idiosyncratic reactions.
• Type A reactions are often linked to polymorphisms affecting drug metabolism or transport.
• Examples of Type A reactions include bleeding due to warfarin dosage and liver toxicity from paracetamol overdose.
• Idiosyncratic (Type B) reactions are unusual or exaggerated responses to drugs in a few individuals and are difficult to study due to their rarity.
• Type B reactions can have serious or fatal consequences for patients.
• Idiosyncratic reactions affect approximately 1 in 1,000 people.
• Type B reactions are not predictable based on known drug pharmacology and not usually dose-related.
• Examples of idiosyncratic reactions include liver toxicity from various drugs at recommended doses and cardiotoxicity.

Details of Idiosyncratic Adverse Drug Reactions

• Idiosyncratic ADRs are not predictable based on known pharmacology.
• Drug concentration may contribute, but it isn't the primary cause.
• These reactions are typically rare, occurring in 1 in 10,000 to 100,000 patients exposed to the drug
• Idiosyncratic ADRs are usually not detected before a drug is licensed.
• Post-marketing surveillance is crucial for detection.
• A relatively large number of widely used drugs are linked to these reactions.
• Older drugs are less likely to be subject to regulatory action.
• Examples of Idiosyncratic ADRs with pharmacogenetic findings include hypersensitivity/skin rash, hepatotoxicity, myopathy and cardiotoxicity.
  • Hypersensitivity or skin rash can be caused by abacavir, carbamazepine or allopurinol.
  • Hepatotoxicity can be caused by flucloxacillin.
  • Myopathy can be caused by statins.
  • Cardiotoxicity can be caused by a variety of compounds.

T-Cell Response and HLA's Role

• HLA is important in T-cell responses.
• MHC stands for multiple histocompatibility complex.
• The presentation results in maturation of T-cells to either helper or cytotoxic cells.
• Cytotoxic T-cells can kill host cells and provoke local cellular damage.
• TCR is the T-cell receptor.
• The type of cell formed depends on the HLA class protein presenting the antigen.
• Different antigens bind to different protein classes.
• Antigens are normally small peptides from bacteria or viruses.
• Sometimes, drugs attach to small host peptides, which antigen presenting cells may recognize as foreign.
• HLA antigens contribute to idiosyncratic reactions, but not all.

HLA Genes

• HLA Class 1 genes (A, B, C) are expressed on most cells and present endogenous antigens to CD8+ cytotoxic T cells.
• HLA Class 1 genes are important in viral immunity and transplant rejection.
• HLA Class 2 genes (DR, DQ, DP) are expressed on antigen-presenting cells (APCs) like dendritic cells, macrophages, and B cells.
• HLA Class 2 genes present exogenous antigens to CD4+ helper T cells for adaptive immune response activation.
• HLA proteins normally present peptide antigens to T cells but may inappropriately present drug-peptide complexes.

Abacavir Hypersensitivity

• Abacavir is a widely used nucleoside reverse-transcriptase inhibitor (NRTI) in combination with antiretroviral therapy (cART) for HIV treatment.
• Approximately 5% of patients develop hypersensitivity reactions that resolve on discontinuation.
• Abacavir hypersensitivity syndrome (AHS) is a life-threatening, immune-mediated reaction.
• Re-exposure to the drug results in a more severe reaction.
• Up to 100% of hypersensitivity cases have one or two HLA B*57:01 alleles.
• Detectable reactions include fever, rash, GI symptoms, and respiratory distress.
• Carriers of HLA B*57:01 are also at risk.
• Abacavir binds to the B*57:01 gene product, inducing a conformational change in the protein.
• This can result in misidentification of self-peptides as foreign, triggering an inappropriate immune response.

Genotyping Data for Abacavir Hypersensitivity

• The Mallal study (2002) found abacavir hypersensitivity generally worsens on re-exposure, has a prevalence of 4-8%, and can be life-threatening.
• Abacavir binding to B*57:01 induces a conformational change, leading to incorrect recognition of self-peptides as foreign by the immune system (Illing and Ostrov et al, 2012).
• The HLA-B*57:01 allele was found to have a:
  • 4.2% frequency in normal controls
  • 2% frequency in HIV-positive tolerant patients
  • 78% frequency in abacavir hypersensitive patients
• The odds ratio is 117 (95% CI: 29-481).

Hughes et al, 2004

• Meta-analysis on studies of abacavir hypersensitivity and HLA genotype.
• 34% experience hypersensitivity from the HLA genotype.

Mechanism for Abacavir Hypersensitivity

• T cells from HLA-B*57:01 positive donors proliferate and differentiate in vitro when stimulated with abacavir, yielding CD-8 positive cytotoxic T-cells.
• Activated abacavir (or a metabolite) binds to the B*57:01 gene product, leading to inappropriate recognition of 'self-peptides' and an inappropriate T cell response.
• AHS reactions result from abacavir directly binding to the peptide-binding groove of HLA-B*57:01.
• This binding alters antigen presentation and triggers an immune response.
• B*57:01 genotyping is now required prior to abacavir treatment, as recommended by the FDA.
• Patients testing positive should receive an alternative NRTI (e.g., tenofovir), while negative patients can use abacavir safely.
• No covalent binding is involved, unlike typical drug-peptide complex interactions.

Steven-Johnson Syndrome (SJS) and Skin Rashes

• Carbamazepine (CBZ) is an anti-epileptic drug used for epilepsy, bipolar disorder, and terminal neuralgia.
• CBZ is associated with severe cutaneous adverse drug reactions (cADRs), including Steven Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN).
• SJS is a widespread rash resulting in significant fluid loss with marked consequences.
• SJS can occur in up to 10% of patients and may be a precursor for hypersensitivity syndrome.

Genetic Associations with SJS

• B*15:02 is strongly linked to SJS/TEN in individuals of East Asian and Southeast Asian descent, especially in Chinese, Indonesian, Thai and Malaysian populations (but not Japanese).
• Carbamazepine interacts with HLA-B*15:02 molecules, leading to T-cell activation and skin necrosis.
• Screening is mandatory in high-risk populations, e.g., Han Chinese, Thai, Malaysians, and Indians.
• B*58:01 is less frequent in Europeans.
• Chinese and Taiwanese patients showing SJS due to this compound are usually positive for HLA-B*15:02.
• Certain other skin rashes relating to CBZ are not B*15:02-related.
• Certain East Asians populations are screened for B*15:02 before CBZ is prescribed.
• Europeans and Japanese show a role for A31:01 (HLA-A31:01).
• Allopurinol is linked to SJS/TEN in individuals of East Asian and Southeast Asian descent.
• Chinese with SJS or related reactions are usually positive for HLA-B*58:01.
• Associated with multiple carbamazepine-induced hypersensitivity reactions, including SJS/TEN.
  • Drug reaction with eosinophilia and systemic symptoms (DRESS) and maculopapular eruptions.
• More common in European and Japanese populations.
• More minor effects are reported in Europeans.
• The effect size with allopurinol is not sufficient to justify genotyping in either population.
• Phenytoin, an aromatic anticonvulsant is associated with a high risk of severe cutaneous adverse reactions (SCAR).
• In South Asian countries, SJS and TEN due to phenytoin correlate to HLA-B*15:02 which isn't as strong as with carbamazepine.
• Several South Asians showed a strong association with CYP2C9*3 & phenytoin-induced SCAR.
• This indicates slower phenytoin metabolism via CYP2C9 and higher systemic exposure predisposes serious skin reactions.

Clinical Implementation

• HLA-B*15:02 testing is required before prescribing carbamazepine in high-risk ethnic groups.
• HLA-A*31:01 testing is recommended in some populations where this allele is prevalent.
• Alternative AEDs (e.g., lamotrigine, levetiracetam, or valproate) should be considered for patients testing positive.

Conclusion

• Pharmacogenetic screening for HLA-B57:01 (abacavir) and HLA-B15:02/HLA-A*31:01 (carbamazepine) improves drug safety by reducing hypersensitivity reactions.
• Implementing these genetic tests in clinical practice ensures personalized medicine, minimizing severe adverse effects while maintaining therapeutic efficacy.

Drug-Induced Liver Injury (DILI)

• Rare but serious idiosyncratic toxicity occurs in 1 of every 10,000 to 100,000 patients with certain drugs.
• Both metabolic and immune factors likely play a role in susceptibility.
• A US-based study showed DILI accounted for 20% of all hospital admissions due to severe liver injury.
  • 50% of acute liver failure cases
  • 75% of them needed a liver transplant

Genetic Associations with DILI

• Haplotypes with DILI were first reported during the 1980s in relation to injury with nitrofurantoin, halothane, and clometacin.
• DRB1*1501 is associated with liver injury due to co-amoxicillin-clavulanate & lumiracoxib.
• Class 1 allele A*33:01 is a risk factor for DILI relating to terbinafine & ticlopidine, as well as other drugs.
• Flucloxacillin can also cause liver injury in some patients.
• HLA-B*5701 is associated with an 80-fold increase in DILI development.
• More common in Europeans than East Asians.
• Hepatotoxicity with ticlopidine appears more common with Japanese patients than Europeans due to association with HLA-A*3303.
• DILI develops several weeks after drug treatment. Therefore, polymorphisms affecting drug metabolism and transport also contribute.

Flucloxacillin

• Beta-lactamase-resistant penicillin with an isoxazolyl ring.
• Widely used to treat staphylococcal infections, especially in the UK, Australia, and Sweden.
• Well-established cause of liver injury.
• Probable second most important cause of DILI in the UK.

GWAS on Flucloxacillin DILI

• 197 cases from UK, Sweden, and Netherlands.
• Population controls selected to eliminate population stratification.
• Illumina IM or human core exome chip was used.
• The strongest signal was with a SNP in HCP5, which tags HLA-B*57:01.
• The association with HLA-B*57:01 is similar to that for abacavir hypersensitivity.
• Sensitivity and specificity of B*57:01 genotyping are lower as a predictor of flucloxacillin DILI than abacavir hypersensitivity.
  • Other, probably non-genetic, risk factors may contribute, including age.
• GWAS provided evidence for a role of ST6GAL1, which encodes ST6 B-galactosamide-a-2,6-sialyltransferase.
  • This may be responsible for B-cell immune responses.
• Augmentin has associations with both HLA 1 and 2 alleles in GWAS studies.
• Amoxicillin is a penicillin (B-lactamase inhibitor) with the allele DRB1*15:01.

HLA and Related Gene Associations with DILI

• Mechanism: Inappropriate T-cell response.
• The mechanism differs from that of abacavir and may involve covalent binding of the drug or a metabolite to the protein.
• The specific HLA protein interacts with a drug complex to inappropriately present a peptide to T cells, causing a reaction.
• This leads to local cellular damage.

Statin Myopathy

• Ranges from mild to very rare but life-threatening rhabdomyolysis.
• GWAS shows an important role in myopathy relating to simvastatin for the SLOC1B1 variant associated with decreased hepatic uptake.
• SLOC1B1 encodes the hepatic statin transporter.
• Higher plasma levels of simvastatin in those with decreased activity *5 variant.
• May result in increased uptake into muscle tissue.

Genetic Associations with Statin Myopathy

• SLOC1B1*5 identified as risk allele (Val174Ala)
• This allele is associated with higher levels of statin in circulation.
• Probably higher plasma level causes muscle toxicity.
• Only 80 cases were required to show this effect.
• The patients were being treated with simvastatin.
• Patients can switch to a different statin.
• D85N, a KCNE1 polymorphism encoding a voltage-gated potassium channel, is seen at a 1% population frequency.
  • More common in individuals who have suffered drug-induced QT prolongation.
  • Odds ratio of 9.

GWAS Detecting Genes Related to Diseases

• Treatment of Hepatitis C virus infection with interferon-a and ribavirin.
  • 50% of patients display a +ve response to this treatment and become essentially virus-
• Polymorphisms adjacent to the IL-28B (interferon gamma-3) gene can predict the response of interferon-a, based on three independent GWAS.
• In a study on bisphosphonate-induced osteonecrosis of the jaw, the CYP2C8 polymorphism had the strongest effect on GWAS.
  • This association is related to the physiological role for CYP2C8 inflammation.

Ion Channels and Serious Adverse Drug Reactions

• A number of drugs can prolong cardiac repolarization.
  • Usually due to blockage of an outward ion channel with K channels the most important in cardiac muscle.
• Some individuals with slight genetic abnormality in K channel have increased risk of sudden death due to drug-induced ventricular fibrillation.
• Change in QT interval
• Normal sinus rhythm compared to the Torsades de pointes.

Candidate Gene Studies on Drug-Induced Long QT

• Paulussen et al, 2004:
  • 100 patients with drug-related long QT syndrome.
  • Sequenced genes for 4 potassium channels and 1 sodium channel.
  • Approx. 10% of patients had non-synonymous polymorphisms in one or more of these channels.
    • KCNE2 - 7 patients
    • KCNE1 - D85N (2 patients)
    • KCNH2 (hERG) - 3 patients
    • KCNQ1 - 3 patients
    • SCN5A - 4 patients
• Nishio et al, 2009:
  • 317 patients
    • KCNE1 only.
    • D85N in 24 of 317 (0.038 or 3.8%) patients compared with 8 out of 496 controls (0.0008 or 0.5%).
• Kaab et al, 2012:
  • 307 cases with Torsade de pointes
    • D85N present in 8.6% of cases but 1.8% of controls.
• Polymorphisms are contributing, but not a complete explanation, as they only represent about 10% of cases.

NOS1AP Gene Affecting Length of QT Interval

• GWAS showed a SNP in NOS1AP (nitric oxide synthase 1 activating protein) affects QT length in a population study.
• The protein regulates intracellular calcium levels.
• A variant of NOS1AP (RS10494366) significantly potentiates the QT prolongation effects of Verapamil.
• NUBPL was also implicated in diQLTs.
• Nitric oxide signaling may affect cardiac repolarization.
• NOS1AP SNP is more common in patients showing QT prolongation in response to several drugs.
• 2 different candidate gene studies agree on this.

GWAS Studies on Drug-Induced Long QT and Torsades de Pointes

• At least 2 have been published, but no genome-wide significance was seen.
  • Likely due to small sample sizes (200 to 300).
• The general conclusion is that common genetic variants are not important predictors for drug-induced cardiotoxicity.
• More difficult to screen for rare variants, possible by exome sequencing.
• Not as much progress has been made on pharmacogenetic basis of cardiotoxicity to date.

Explore the differences between intrinsic (Type A) and idiosyncratic (Type B) adverse drug reactions. Type A reactions are predictable and dose-dependent, while Type B reactions are rare, unpredictable, and not related to the drug's known pharmacology. Learn about examples and implications of these reactions.