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Idiosyncratic drug reactions (IDR) remain an important cause of late development program failure or drug withdrawal. They represent a significant economic cost and patient burden. Although our understanding of IDR continues to grow, our ability to predict and avoid these reactions remains unacceptably poor. The intent of this chapter is to review approaches that may be used during lead optimization to minimize the likelihood of producing compounds for development that will have a high IDR liability.

Defining Idiosyncratic Drug Reactions

A clear definition and an understanding of how that definition is applied are critical for a rational discussion of prediction of idiosyncratic reactions (see Table 1 for examples of IDR). The definition of idiosyncratic reactions that will form the basis for the following discussion is:

An idiosyncratic adverse drug reaction is an uncommon adverse reaction to a drug that is not related to the pharmacological properties of the drug, that occurs at therapeutic doses and/or serum concentrations, and will not occur in the majority of individuals despite increasing the dose to otherwise toxic concentrations.

The following characteristics are also used to identify adverse drug reactions as idiosyncratic:

• They are dependent on the chemical, not the pharmacological properties of the drug.

• They are highly host-dependent. An idiosyncratic reaction is dependent on a specific interaction between the chemical properties of the drug and the host.

• There is no simple or classical dose-response relationship for the clinical reaction.

• IDR usually occur at frequencies of less than 1/100, and often at frequencies of 1/1000 or 1/10,000. However, rates of up to 50% in specific populations have been reported.

• They can not be predictably reproduced in animals. Idiosyncratic reactions do occur in animals, but they can not be reliably reproduced in an experimental setting with a general laboratory population. If the reaction was reliably produced in pre-clinical studies, the compound would likely not be developed and the reaction would not be identified as being idiosyncratic in humans.

• The mechanism is unknown. This is certainly true for the majority of idiosyncratic reactions. However, an understanding of the mechanism does not preclude a reaction from being defined as idiosyncratic if the primary characteristics of an IDR are observed.

Drug

Predominant Manifestation of Drug Reaction

Sulfonamides

Systemic hypersensitivity syndrome reaction, including dermatopathy, fever, and hepatitis; Stevens-Johnson Syndrome; toxic epidermal necrolysis

Aromatic anticonvulsants

Systemic hypersensitivity syndrome reactions, including dermatopathy, fever, and hepatitis; Stevens-Johnson Syndrome; toxic epidermal necrolysis

Halothane

Hepatitis with systemic signs Malignant hyperthermia

Tienilic acid

Hepatitis

Abacavir

Fever, dermatopathy, malaise, gastrointestinal disturbances

Dihydralazine

Hepatitis

Diclofenac

Hepatitis

Ibufenac

Hepatitis

Table 1. Examples of well-recognized idiosyncratic drug reactions

Table 1. Examples of well-recognized idiosyncratic drug reactions

The clinical presentation of idiosyncratic reactions and the target organ can be highly variable. Common target organs include the skin, liver, kidney, and hematological system. Patients may present with one or more target organs affected. Some drugs target primarily one organ system (e.g. clozapine and agranulocytosis; halothane and hepatitis) while others target multiple organs and have multiple clinical presentations.

Idiosyncratic drug reactions commonly present with signs consistent with an immune-mediated pathogenesis, including delayed onset (usually from 1 to 6 weeks after start of therapy), fever, eosinophilia, dermatopathy and multi-organ toxicity. A more rapid onset of clinical signs is often observed on re-challenge, also consistent with an immune-mediated reaction. Terms such as the idiosyncratic hypersensitivity syndrome reaction, drug-induced immune-mediated disease, or drug-induced lupus, depending on the particular constellation of clinical signs, are used to describe IDR. Demonstration of antibodies or reactive T-cells recognizing the drug, drug-modified proteins, or autologous proteins are required to truly meet the criteria of immune-mediated disease, but many IDR are assumed to have an immunological basis solely on the basis of clinical signs. Many users of the term "idiosyncratic reaction" intend to refer specifically to the subset of idiosyncratic reactions that have an immunological basis. It is generally the most important group of idiosyncratic reactions from a drug development perspective. The evidence for an immunological basis of idiosyncratic reactions will be discussed in more detail below.

Some authors define the term idiosyncratic drug reaction as a genetically determined abnormal reactivity to a chemical or as a rare toxicity of an unknown mechanism.

These definitions share some similarities with the definition of IDR presented above, but they capture different populations of adverse drug reactions. Genetically determined abnormal reactivity to a chemical captures not only immune-mediate idiosyncratic adverse drug reactions, but also drug reactions such as azathioprine hematotoxicity in thiopurine methytransferase deficient individuals (Evans 2004; Farrell 2002; Lennard et al. 1989; Stravitz and Sanyal 2003) and perhexilene hepatotoxicity in CYP2D6 deficient individuals (Farrell 2002; Stravitz and Sanyal 2003). I prefer to use the term hypersusceptibility to characterize these reactions.

Hypersusceptibility describes those individuals that are particularly susceptible to dose-dependent toxicities. Individual susceptibility may be determined by genetic factors, but the advers reaction can be produced in more individuals by increasing the dose or serum concentration, and it can be produced in a dose-dependent manner in experimental animals. Environmental exposures and drug interactions can also lead to hypersusceptibility. Additional examples of hypersusceptibilities are given in Table 2. While I do not consider these reactions to be idiosyncratic, the prediction of potential hypersusceptible individuals in the population, genetic or environmentally-induced, is an important part of drug development and the presence of hypersusceptibility can certainly lead to uncommon adverse events that can result in drug withdrawal.

Drug

Putatitive Susceptible Population

6-mercaptopurine/ azathioprine

Patients deficient in thiopurine methyltransferase are dramatically susceptible to hematotoxicity

Acetaminophen

Alcoholics demonstrate hypersusceptibility to acetaminophen hepatotoxicity

Perhexiline

CYP2D6 deficient individuals show enhanced susceptibility to hepatotoxicity

Dapsone and other arylamines

Glucose-6-phosphate dehydrogenase deficiency increases susceptibility to methemoglobinemia/hemolytic anemia

Valproic acid

Unknown susceptibility factors for hepatotoxicity. Some consider this to be idiosyncratic toxicity but mild liver damage can be dose-dependently and predictably produced in animal models, and there is little evidence of an immunological component in humans with valproate hepatotoxicity. Classification still debateable.

Terfenadine

Patients taking ketoconazole show hypersusceptibility to prolonged QT-interval as a result of a drug interaction

Phenytoin

Patients homozygous for CYP2C9*3 allele show marked susceptibility to phenytoin pharmacological toxicity

Table 2. Examples of Drug Hypersusceptibility

Table 2. Examples of Drug Hypersusceptibility

Idiosyncratic reactions to drugs do occur in animals, often with a similar clinical presentation to humans (Cribb et al. 1996). However, it is rare that they can be reliably induced in the typical laboratory animal population. This has been a significant limiting factor in understanding the molecular events involved in idiosyncratic reactions. Any potential animal models appear to be compound specific and there are no general models that are currently useful. Therefore, animal models will not be further discussed in this chapter.

Predicting patients versus predicting compounds

It is important to differentiate between predicting which patients will experience idiosyncratic reactions and predicting which compounds will be associated with an unacceptably high incidence of idiosyncratic reactions. Lead optimization occurs prior to human exposure and assessment of individual risk is neither required nor, with our current understanding, applicable at this stage of drug development. Understanding individual risk may be important during clinical development and will ultimately help us in our efforts to predict compounds that will be associated with idiosyncratic reactions but is not an integral part of the lead optimization process.

There are many marketed compounds that will cause idiosyncratic reactions but not at an incidence or of a severity that limits their use. While the ultimate goal is to eliminate idiosyncratic reactions associated with new chemical entities, a reduction to a clinically acceptable incidence or severity may serve as an intermediate goal. The only approach currently available is to identify the characteristics of compounds with a higher probability versus those with a lower probability of triggering idiosyncratic reactions. These characteristics can then be used to optimize lead compounds.

Figure 1. A general paradigm for the pathogenesis of idiosyncratic reactions.

We must have a working concept of the pathogenesis of idiosyncratic reactions if we are to develop a paradigm for optimizing lead compounds to minimize the risk of producing a drug that induces IDR. For the purposes of this chapter, we will focus on idiosyncratic reactions in which the clinical manifestations result from cellular damage to an identified organ or tissue. Although not universally accepted, the majority of experts agree that a pathological immune response underlies the clinical manifestations of the majority of idiosyncratic reactions where cellular or organ damage is an integral part of the pathogenesis. Therefore, this chapter will discuss approaches that may be useful in helping to predict and/or eliminate compounds that may be associated with an unacceptably high frequency of immune-mediated idiosyncratic reactions.

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