Toxicological Reviews

, Volume 23, Issue 4, pp 265–280

Drug-Induced Hypersensitivity

Role in Drug Development
Review Article


Drug-induced hypersensitivity is an adverse reaction, characterised by damaging immune-mediated responses, initiated by medicine given at therapeutic doses for prevention, diagnosis or treatment. Immune-mediated drug hypersensitivity accounts for 6–10% of the adverse drug reactions, which rank between the fourth and sixth leading causes of death in the US. With <10% of all adverse drug reactions reported, the magnitude of the problem is significant, with estimates of costs >$US30 billion annually in the US (1995 value). In addition, the costs of not determining the potential of a drug to produce hypersensitivity in the pre-clinical phase of drug development can be substantial. It has been estimated that the pre-clinical phase and clinical phase I, phase II and phase III costs are approximately $US6 million, $US12 million, $US12 million and $US100 million per drug, respectively (1999 values). It is important that investigational drugs with the potential to produce hypersensitivity reactions be identified as early in the development process as possible. Some adverse reactions to drugs can be avoided if drug-drug interactions are known or if there is a structure-activity relationship established. However, these methods are inadequate. Appropriate animal models of drug-induced hypersensitivity are needed, especially because hypersensitivity has been cited as the leading reason for taking drugs off the market.

It is of critical importance to be able to predict hypersensitivity reactions to drugs. Most anaphylactic reactions occur in atopic individuals. Similarly, patients who have experienced other hypersensitivity reactions are more likely to have recurrent reactions. Therefore, animal models should be considered that predispose the animal to the reaction, such as the use of appropriate adjuvants and species. Using known positive controls of varying strengths, the investigator can rank the reaction against the positive controls as standards. This approach might yield greater results in a shorter period of time than using novel models. For the greatest safety, use of well understood models that have been thoroughly validated is imperative.


  1. 1.
    World Health Organization. International drug monitoring: the role of the hospital. Geneva: World Health Organization, 1966Google Scholar
  2. 2.
    Coombs RRA, Gell PGH. Classification of allergic reactions responsible for clinical hypersensitivity and disease. In: Gell PGH, Coombs RRA, editors. Clinical aspects of immunology. 2nd ed. Oxford: Blackwell Scientific Publications, 1968: 575–96Google Scholar
  3. 3.
    Naisbitt DJ, Gordon SF, Pirmohamed M, et al. Immunological principles of adverse drug reactions: the initiation and propagation of immune responses elicited by drug treatment. Drug Saf 2000; 23: 483–507PubMedCrossRefGoogle Scholar
  4. 4.
    Ioannidis JPA, Lau J. Completeness of safety reporting in randomized trials. JAMA 2001; 285: 437–43PubMedCrossRefGoogle Scholar
  5. 5.
    Brewer T, Colditz GA. Postmarketing surveillance and adverse drug reactions: current perspectives and future needs. JAMA 1999; 281: 824–9PubMedCrossRefGoogle Scholar
  6. 6.
    Bates DW. Drugs and adverse drug reactions: how worried should we be? JAMA 1998; 279: 1216–7PubMedCrossRefGoogle Scholar
  7. 7.
    Johnson JA, Bootman JL. Drug-related morbidity and mortality: a cost-of-illness model. Arch Intern Med 1995; 155: 1949–56PubMedCrossRefGoogle Scholar
  8. 8.
    Adkinson Jr NF, Essayan D, Gruchalla R, et al. Task force report: future research needs for the prevention and management of immune-mediated drug hypersensitivity reactions. J Allergy Clin Immunol 2002; 109: S461PubMedCrossRefGoogle Scholar
  9. 9.
    Wood AJJ. Thrombotic thrombocytopenic purpura and clopidogrel: a need for new approaches to drug safety. N Engl J Med 2000; 342: 1824–6PubMedCrossRefGoogle Scholar
  10. 10.
    Lasser KE, Allen PD, Woolhandler SJ, et al. Timing of new black box warnings and withdrawals for prescription medications. JAMA 2002; 287: 2215–20PubMedCrossRefGoogle Scholar
  11. 11.
    Neugut AI, Ghatak AT, Miller RL. Anaphylaxis in the United States: an investigation into its epidemiology. Arch Intern Med 2001; 161: 15–21PubMedCrossRefGoogle Scholar
  12. 12.
    Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998; 279: 1200–5PubMedCrossRefGoogle Scholar
  13. 13.
    Payne MP, Walsh PT. Structure-activity relationships for skin sensitization potential: development of structural alerts for use in knowledge-based toxicity prediction systems. J Chem Inf Comput Sci 1994; 34: 154–61PubMedCrossRefGoogle Scholar
  14. 14.
    Karol MH, Graham C, Gealy R, et al. Structure-activity relationships and computer-assisted analysis of respiratory sensitization potential. Toxicol Lett 1996; 86: 187–91PubMedCrossRefGoogle Scholar
  15. 15.
    Pease CK, Basketter DA, Patlewicz GY. Contact allergy: the role of skin chemistry and metabolism. Clin Exp Dermatol 2003; 28: 177–83CrossRefGoogle Scholar
  16. 16.
    Olson H, Betton G, Robinson D, et al. Concordance of the toxicity of pharmaceuticals in humans and in animals. Reg Toxicol Pharmacol 2000; 32: 56–67CrossRefGoogle Scholar
  17. 17.
    Uetrecht JP. The role of leukocyte-generated reactive metabolites in the pathogenesis of idiosyncratic drug reactions. Drug Metab Rev 1992; 24: 299–366PubMedCrossRefGoogle Scholar
  18. 18.
    Tizard IR, editor. Immunology. 2nd ed. Philadelphia (PA): Saunders College Publishing, 1988: 455–529Google Scholar
  19. 19.
    Golub ES, Green DR. Immunology: a synthesis. 2nd ed. Sunderland (MA): Sinauer Associates Inc., 1991: 596–642Google Scholar
  20. 20.
    Ahlstedt S. Penicillin allergy: can the incidence be reduced. Allergy 1984; 39: 151–64PubMedCrossRefGoogle Scholar
  21. 21.
    Tizard IR, editor. Immunology. 2nd ed. Philadelphia (PA): Saunders College Publishing, 1988: 18–24Google Scholar
  22. 22.
    Park BK, Pirmohamed M, Kitteringham NR. Role of drug disposition in drug hypersensitivity: a chemical, molecular, and clinical perspective. Chem Res Toxicol 1998; 11: 969–88PubMedCrossRefGoogle Scholar
  23. 23.
    Griem P, Wulferink M, Sachs B, et al. Allergic and autoimmune reactions to xenobiotics: how do they arise? Immunol Today 1998; 19: 133–41PubMedGoogle Scholar
  24. 24.
    Parkinson A. Biotransformation of xenobiotics. In: Klaassen CD, editor. Casaratt and Doull’s Toxicology: the basic science of poisons. 5th ed. New York: McGraw Hill, 1996: 113–86Google Scholar
  25. 25.
    Schnyder B, Mauri-Hellweg D, Zanni M, et al. Direct, MHC-dependent presentation of the drug sulfamethoxazole to human T-cell clones. J Clin Invest 1997; 100: 136–41PubMedCrossRefGoogle Scholar
  26. 26.
    Pichler WJ. Pharmacological interaction of drugs with antigen-specific immune receptors: the p-i concept. Curr Opin Allergy Clin Immunol 2002; 2: 301–5PubMedCrossRefGoogle Scholar
  27. 27.
    Gruchalla RS. Drug allergy. J Allergy Clin Immunol 2003; 111: S548PubMedCrossRefGoogle Scholar
  28. 28.
    Kemp SF, Lockey RF, Wolf BL, et al. Anaphylaxis: a review of 266 cases. Arch Intern Med 1995; 155: 1749–54PubMedCrossRefGoogle Scholar
  29. 29.
    Suzuki Y, Inaga R, Aono T, et al. Human herpesvirus 6 infection as a risk factor for the development of severe drug-induced hypersensitivity syndrome. Arch Dermatol 1996; 134: 1108–12CrossRefGoogle Scholar
  30. 30.
    Antonen JA, Markula KP, Pertovaara MI, et al. Adverse drug reactions in Sjogren syndrome: frequent allergic reactions and a specific trimethoprim-associated systemic reaction. Scand J Rheumatol 1999; 28: 157–9PubMedCrossRefGoogle Scholar
  31. 31.
    Matzinger P. An innate sense of danger. Semin Immunol 1998; 10: 399–415PubMedCrossRefGoogle Scholar
  32. 32.
    Golub ES, Green DR. Immunology: a synthesis. 2nd ed. Sunderland (MA): Sinauer Associates Inc., 1991: 535Google Scholar
  33. 33.
    Albers R, van der Pijl A, Bol M, et al. Stress proteins (HSP) and chemical-induced autoimmunity. Toxicol Appl Pharmacol 1996; 140: 70–6PubMedCrossRefGoogle Scholar
  34. 34.
    Benoit Y, Chadenson O, Ducloux B, et al. Hypersensitivity to Althesin infusion: measurement of complement involvement. Anaesthesia 1983; 38: 1079–81PubMedCrossRefGoogle Scholar
  35. 35.
    Rosnow CE, Moss J, Philbin DM, et al. Histamine release during morphine and fentanyl anaesthesia. Anesthesiology 1982; 56: 93–6CrossRefGoogle Scholar
  36. 36.
    Manning ME, Stevenson DD. Pseudo-allergic drug reactions: aspirin, nonsteroidal anti-inflammatory drugs, dyes, additives and preservatives. Immunol Allergy Clin North Am 1991; 11: 659–78Google Scholar
  37. 37.
    Furst SM, Gandolfi AJ. Interaction of lymphocytes with Kupffer cells from halothane-exposed guinea pigs. Int Arch Allergy Immunol 1997; 114: 46–53PubMedCrossRefGoogle Scholar
  38. 38.
    Furst SM, Luedke D, Gaw HH, et al. Demonstration of a cellular immune response in halothane-exposed guinea pigs. Toxicol Appl Pharmacol 1997; 143: 245–55PubMedCrossRefGoogle Scholar
  39. 39.
    Zimmerman HJ, Lewis JH, Ishak KG, et al. Ticrynafen-associated hepatic injury: analysis of 340 cases. Hepatology 1984; 4: 315–23PubMedCrossRefGoogle Scholar
  40. 40.
    Breen EG, McNicholl J, Cosgrove E, et al. Fatal hepatitis associated with diclofenac. Gut 1986; 27: 1390–3PubMedCrossRefGoogle Scholar
  41. 41.
    Richerson HB, Seidenfeld JJ, Ratajczak HV, et al. Chronic experimental interstitial pneumonitis in the rabbit. Am Rev Respir Dis 1978; 117: 5–13PubMedGoogle Scholar
  42. 42.
    Naldi L, Conforti A, Venegoni M, et al. Cutaneous reactions to drugs: an analysis of spontaneous reports in four Italian regions. Br J Clin Pharmacol 1999; 48: 839–46PubMedCrossRefGoogle Scholar
  43. 43.
    Bigby M, Jick S, Jick H, et al. Drug-induced cutaneous reactions: a report from the Boston Collaborative Drug Surveillance Program on 15,438 consecutive inpatients, 1975 to 1982. JAMA 1986; 256: 3358–63PubMedCrossRefGoogle Scholar
  44. 44.
    Roujeau JC, Kelly JP, Naldi L, et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 1995; 333: 1600–7PubMedCrossRefGoogle Scholar
  45. 45.
    Ahlstdet S, Edstrom B, Svard PO, et al. New aspects on antigens in penicillin allergy. Crit Rev Toxicol 1980; 7: 219–77CrossRefGoogle Scholar
  46. 46.
    Pichler W, Yavalkar N, Schmid S, et al. Pathogenesis of drug-induced exanthems. Allergy 2002; 57: 884–93PubMedCrossRefGoogle Scholar
  47. 47.
    Sarlo K, Clark ED. A tier approach for evaluating the respiratory allergenicity of low molecular weight chemicals. Fundam Appl Toxicol 1992; 18: 107–14PubMedCrossRefGoogle Scholar
  48. 48.
    Calabrese EJ. Suitability of animal models for predictive toxicology: theoretical and practical considerations. Drug Metab Rev 1984; 15: 505–23PubMedCrossRefGoogle Scholar
  49. 49.
    Garattini S. Toxic effects of chemicals: difficulties in extrapolating data from animals to man. Ann Rev Toxicol 1985; 16: 1–29CrossRefGoogle Scholar
  50. 50.
    Ratajczak HV, Lange RW, Sothern RB, et al. Surgical influence on murine immunity and tumor growth: relationship of body temperature and hormones with splenocytes [published erratum appears in Proc Soc Exp Biol Med 1992; 200: 448–51]. Proc Soc Exp Biol Med 1992; 199: 432–40PubMedGoogle Scholar
  51. 51.
    Sothern RB, Roitman-Johnson B. Biological rhythms and immune function. In: Ader R, Feiten DL, Cohen N, editors. Psychoneuroimmunology. 3rd ed. San Diego (CA): Academic Press, 2001: 1, 445–79Google Scholar
  52. 52.
    Maestroni GJM, Conti A, Pierpaoli W. Role of the pineal gland in immunity. J Neuroimmunol 1986; 13: 19–30PubMedCrossRefGoogle Scholar
  53. 53.
    Sanchez de la Pena S. The feedsideward of cephalo-adrenal immune interactions. Chronobiologia 1993; 20: 1–52PubMedGoogle Scholar
  54. 54.
    Zbinden G. Predictive value of animal studies in toxicology. Reg Toxicol Pharmacol 1991; 14: 167–77CrossRefGoogle Scholar
  55. 55.
    Verdier F, Chazal I, Descotes J. Anaphylaxis models in the guinea-pig. Toxicology 1994; 93: 55–61PubMedCrossRefGoogle Scholar
  56. 56.
    Landsteiner K, Jacobs J. Studies on the sensitization of animals with simple chemical compounds. J Exp Med 1935; 61: 643–57PubMedCrossRefGoogle Scholar
  57. 57.
    Wierda D, Smith HW, Zwickl CM. Immunogenicity of biopharmaceuticals in laboratory animals. Toxicology 2001; 158: 71–4PubMedCrossRefGoogle Scholar
  58. 58.
    Vial T, Descotes J. Contact sensitization assays in guinea-pigs: are they predictive of the potential for systemic allergic reactions? Toxicology 1994; 93: 63–75PubMedCrossRefGoogle Scholar
  59. 59.
    Weaver JL, Staten D, Hastings KL. An evaluation of guinea pig hypersensitivity test for ability to detect systemic hypersensitivity potential of drugs [abstract]. Toxicologist 1999; 48: 316Google Scholar
  60. 60.
    Albers R, Breeders A, van Der Pijl A, et al. The use of reporter antigens in the popliteal lymph node assay to assess immunomodulation by chemicals. Toxicol Appl Pharmacol 1997; 143: 102–9PubMedCrossRefGoogle Scholar
  61. 61.
    Hastings KL. Pre-clinical methods for detecting the hypersensitivity potential of Pharmaceuticals: regulatory considerations. Toxicology 2001; 158: 85–9PubMedCrossRefGoogle Scholar
  62. 62.
    Austen KF, Humphrey JH. In vitro studies of the mechanism of anaphylaxis. In: Dixon Jr JH, Humphrey JH, editors. Advances in immunology. New York: Academic Press, 1963: 1–96Google Scholar
  63. 63.
    Davis BD, Dulbecco R, Eisen HN, et al., editors. Microbiology. 2nd ed. New York: Harper and Row, 1973: 539Google Scholar
  64. 64.
    Coenen TMM, Ratajczak HV. Equal allergenic potency of beta-lactam antibiotics produced by chemical or enzymatic manufacturing: mouse IgE test. Int Arch Allergy Immunol 2001; 126: 173–8PubMedCrossRefGoogle Scholar
  65. 65.
    Mota I, Wong D. Homologous and heterologous passive cutaneous anaphylactic activity of mouse antisera during the course of immunization. Life Sci 1969; 8: 813–20PubMedCrossRefGoogle Scholar
  66. 66.
    Kimber I, Hilton J, Basketter DA, et al. Predictive testing for respiratory sensitization in the mouse. Toxicol Lett 1996; 86: 193–8PubMedCrossRefGoogle Scholar
  67. 67.
    Hilton J, Dearman RJ, Boylett MS, et al. The mouse IgE test for the identification of potential chemical respiratory allergens: considerations of stability and controls. J Appl Toxicol 1996; 16: 165–70PubMedCrossRefGoogle Scholar
  68. 68.
    Dearman RJ, Skinner RA, Humphreys NE, et al. Methods for the identification of chemical respiratory allergens in rodents: comparisons of cytokine profiling with induced changes in serum IgE. J Appl Toxicol 2003; 23: 199–207PubMedCrossRefGoogle Scholar
  69. 69.
    Dearman RJ, Kimber I. Cytokine fingerprinting and hazard assessment of chemical respiratory allergy. J Appl Toxicol 2001; 21: 153–63PubMedCrossRefGoogle Scholar
  70. 70.
    Ritz HL, Evans BLB, Bruce RD, et al. Respiratory and immunological responses of guinea pigs to enzyme containing detergents: a comparison of intratracheal and inhalation modes of exposure. Fundam Appl Toxicol 1993; 21: 31–7PubMedCrossRefGoogle Scholar
  71. 71.
    Kawabata TT, Babcock LS, Gauggel DL, et al. Optimization and validation of an ELISA to measure specific guinea pig IgG1 antibody as an alternative to the in vivo passive cutaneous anaphylaxis assay. Fundam Appl Toxicol 1995; 24: 238–46PubMedCrossRefGoogle Scholar
  72. 72.
    Regel JF, Klos A. Minor role of the C3a receptor in systemic anaphylaxis in the guinea pig. Immunopharmacology 2000; 46: 15–28CrossRefGoogle Scholar
  73. 73.
    Descotes J, Verdier F. Popliteal lymph node assay. In: Burleson GR, Dean JH, Munson AE, editors. Methods in immunotoxicology. New York: Wiley-Liss, 1995; 1: 189–96Google Scholar
  74. 74.
    Buehler EV. Prospective testing for delayed contact hypersensitivity in guinea pigs: the Buehler method. In: Burleson GR, Dean JH, Munson AE, editors. Methods in immunotoxicology. New York: Wiley-Liss, 1995; 2: 343–56Google Scholar
  75. 75.
    Magnusson B, Kligman AM. The identification of contact allergens by animal assay. The guinea pig maximization test. J Invest Dermatol 1969; 52: 268–76PubMedGoogle Scholar
  76. 76.
    Draize JH, Woodard G, Calvery HO. Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J Pharmacol Exp Ther 1944; 82: 337–90Google Scholar
  77. 77.
    Kimber I. The local lymph node assay. In: Burleson GR, Dean JH, Munson AE, editors. Methods in immunotoxicology. New York: Wiley-Liss, 1995: 279–90Google Scholar
  78. 78.
    Gad SC, Dunn BJ, Dobbs DW, et al. Development and validation of an alternative dermal sensitization test: the mouse ear swelling test (MEST). Toxicol Appl Pharmacol 1986; 84: 93–114PubMedCrossRefGoogle Scholar
  79. 79.
    Descotes J. Identification of contact allergens: the mouse ear sensitization assay. J Toxicol Cutaneous Ocul Toxicol 1988; 7: 263–72CrossRefGoogle Scholar
  80. 80.
    Basketter DA, Scholes EW, Chamberlain M, et al. An alternative strategy to the use of guinea pigs for the identification of skin sensitization hazard. Food Chem Toxicol 1995; 33: 1051–6PubMedCrossRefGoogle Scholar
  81. 81.
    Friedman MA, Woodcock J, Lumpkin MM, et al. The safety of newly approved medicines: do recent market removals mean there is a problem? JAMA 1999; 281: 1728–34PubMedCrossRefGoogle Scholar
  82. 82.
    Irey NS. When is a disease drug induced? In: Riddell RH, editor. Pathology of drug-induced and toxic diseases. New York: Churchill Livingstone, 1982: 1–18Google Scholar
  83. 83.
    Gradle C, Ratajczak H, Fresco R, et al. Definition of the pulmonary antibody response to ovalbumin following local challenge in systemically immunized rats. Proc Soc Exp Biol Med 1988; 188: 61–9PubMedGoogle Scholar
  84. 84.
    Ratajczak HV, Richards DW, Richerson HB. Systemic and local lymphocyte responses in experimental hypersensitivity pneumonitis. Am Rev Respir Dis 1980; 122: 761–8PubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Boehringer Ingelheim Pharmaceuticals Inc.RidgefieldUSA

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