IDIOSYCRATIC DRUG REACTIONS (IDR)

Idiosyncratic - defined as "specific to an individual"

Idiosyncratic drug reaction (IDR) - an adverse drug reaction that does not

1) occur in most people within the range of doses used clinically2) involve known pharmacological effects of the drug 3) appear to have any obvious relationship between dose and treatment duration

Clinical significance - about 0.03% of all adverse drug reactions are idiosyncratic

General Comments about IDR

IDR are difficult to deal with as current testing is not effective in predicting their risk

Characteristics of IDR

Time to onset -an important characteristic of IDR is a delay between initiating drug therapy and the onset of the adverse reaction. Typically, delay in onset is a week or more on first exposure

Typical delay of onset is different for 1) different types of IDR and 2) different drugs

Maculopapular rashes - occur after 1-2 weeks of treatmentIDR-induced hepatitis - occurs after 1-2 months of treatmentIDR-induced lupus - occurs after 3-6 month or more than 12 months

NOTE: in contrast to the first exposure, re-exposure to the offending drug can produce signs/symptoms of an IDR in a shorter period of time. However, sometimes the onset of symptoms upon rechallenge can be delayed

Likelihood of an IDR is related to Drug-related and Patient-related risk factors. IDR occur upon convergence of these risk factors

Drug-related factors - metabolism, bioactivation and covalent binding, inhibition of key cell functions

Patient-related factors - underlying disease, age, gender, nutritional status, activation of the innate immune system, physical activity and genetic predisposition

Adaptation/Tolerance

If a drug causes an IDR such as liver failure (e.g. 0.01%) in a small number of patients, it usually causes a much higher incidence (1-2%) of liver transaminase activity (generally indicative of liver injury).

However, in most patients, the liver transaminase activity is transient and returns to normal despite continued use of the drug

Pathogenesis of IDR - primarily due to an immune-mediated mechanism (?)

Evidence suggesting that the idiosyncratic nature of IDR is IMMUNE-MEDIATED is:

Delay between initiation of drug therapy and onset of the IDR - most likely due to the time required for expansion of B and/or T cells specific for a given drug to produce a clinically relevant immune response

Rapid onset upon rechallenge with the offending drug; however, lack of a rapid onset after rechallenge DOES NOT prove that an IDR is not immune-mediated response

Presence of antibodies against the drug - however, antibodies may not be pathogenic

HLA genotype strongly associated with risk of specific IDR (only proven for a limited number of cases)

NOTE: not all IDR may be immune-mediated; genetic and environmental factors, alone or in combination, may be responsible

The IDR listed below are most likely immune-mediated:

Drug-induced autoimmune reactionsAntibody-mediated cytopenias (e.g. thrombo-, agranulo, neutro)Generalized hypersensitivity reactionsDrug-associated skin rashesHepatitis associated with drug antibodies

Mechanistic Hypotheses for IDR

General consensus is that many IDR are Immune-mediated; THUS, MOST OF THE MECHANISTIC HYPOTHESES HAVE AN IMMUNE BASIS

Chemically reactive metabolites are responsible for many IDR (based on strong circumstantial evidence) - although reactive metabolites may not always be required)

Hapten Hypothesis

Chemically reactive drug (or more likely a reactive metabolite) COVALENTLY binds to a protein or carrier molecule - this forms an adduct or HAPTEN.

Hapten is recognized as FOREIGN OR NON-SELF by the immune system and generates an immune response

Carrier-Hapten complex must undergo endocytosis by APC, where it is processed and presented in the groove of the MHC II protein to T cells - this recognition of the Carrier-Hapten by the T cell receptor is SIGNAL 1

REMEMBER:

1. Most small molecules (< 1000 daltons) DO NOT bind with sufficient affinity to the MHC and

2. If their interaction with proteins were readily reversible, they could not survive antigen processing

Most drugs that produce a high incidence of IDR are metabolized to a reactive metabolite that could bind to a protein or carrier and act as a hapten

However, NOT ALL DRUGS that are metabolized to a reactive metabolite are associated with a significant incidence of IDR. There are no data indicating a correlation between amount of covalent binding and risk a drug will produce a high incidence of IDR

Danger Hypothesis

This was proposed as:

1. Hapten alone is insufficient to produce a complete immune response. Primary determinant of an immune response is not non-self but DANGER

2. Foreign proteins do not generate a signal in the absence of an ADJUVANT, which activates the antigen presenting cells (APC)

3. It is inefficient to respond to something unless it was causing injury or damage to the organism

Components of the Danger Hypothesis

1. Injured tissue determines if an immune response will occur and if it does, what type of response will occur

2. Requires presence of Signal 1 and Signal 2 (Danger signal). The danger signal is derived from stressed cells that release various molecules (e.g. HSP, cytokines) that activate APC and subsequent upregulation of co-stimulatory molecules that activate Th1 cells, providing the second signal

3. Danger signals – likely to be endogenous (may also come from infectious agents, particularly viruses) and different for types of stress and different types of cells

Pharmacological Intervention (PI) Hypothesis

Drugs do not need to be metabolized or covalently bound to a carrier

Drugs bind reversible to the MHC-T cell receptor complex (similar to a superantigen) and this can stimulate an immune response. Lymphocytes respond to what initiated the immune response

Above information from:

Annu Rev Pharmacol Toxicol 47:513-547, 2007Annu Rev Immunol 12:991-1045, 1994Chem Res Toxicol 21:84-92, 2008AAPS Journal 8:E46-E54, 2008