Pharmacogenomics of off-target adverse drug reactions

Abstract

Off-target adverse drug reactions (ADRs) are associated with significant morbidity and costs to the healthcare system, and their occurrence is not predictable based on the known pharmacological action of the drug's therapeutic effect. Off-target ADRs may or may not be associated with immunological memory, although they can manifest with a variety of shared clinical features, including maculopapular exanthema, severe cutaneous adverse reactions (SCARs), angioedema, pruritus and bronchospasm. Discovery of specific genes associated with a particular ADR phenotype is a foundational component of clinical translation into screening programmes for their prevention. In this review, genetic associations of off-target drug-induced ADRs that have a clinical phenotype suggestive of an immunologically mediated process and their mechanisms are highlighted. A significant proportion of these reactions lack immunological memory and current data are informative for these ADRs with regard to disease pathophysiology, therapeutic targets and biomarkers which may identify patients at greatest risk. Although many serious delayed immune-mediated (IM)-ADRs show strong human leukocyte antigen associations, only a small subset have successfully been implemented in screening programmes. More recently, other factors, such as drug metabolism, have been shown to contribute to the risk of the IM-ADR. In the future, pharmacogenomic targets and an understanding of how they interact with drugs to cause ADRs will be applied to drug design and preclinical testing, and this will allow selection of optimal therapy to improve patient safety.

Keywords: abacavir; adverse drug reaction; aspirin-exacerbated respiratory disease; carbamazepine; human leukocyte antigen; pharmacogenomics.

Figure 1

Classification of adverse drug reactions. Adverse drug reactions can be classified according to their on‐target vs. off‐target interactions between the drug and cellular components. Contrary to previous belief, both on‐target and off‐target effects can demonstrate concentration–exposure relationships that may differ between individuals based on acquired or genetic host factors. The interaction between the drug and the target may relate to both the dose and/or duration of treatment. The classical description of on‐target reactions is an augmentation of the known primary therapeutic and pharmacological action of a drug (e.g. bleeding related to warfarin), and off‐target effects can occur by mechanisms that are both directly immune mediated and associated with immunological memory of varied duration (drug allergy), and mechanisms without a direct immunological effect and without immunological memory that may have an ‘immunological phenotype’. These latter reactions are often mediated through a pharmacological interaction (e.g. aspirin‐exacerbated respiratory disease or the non‐IgE‐mediated mast‐cell activation seen with fluoroquinolones and opioids). Off‐target reactions that result from a primary pharmacological interaction are often dose dependent, whereas immunologically mediated off‐target reactions associated with immunological memory can be both dose dependent (T‐cell‐mediated reactions) or dose independent (recognition and amplification of small amounts of antigen in the case of IgE‐mediated reactions). Predisposition to both on‐target and off‐target reactions is driven not only by genetic variation, but also by ecological factors that can vary over the course of an individual's lifetime (adapted from Phillips 13 and White et al. 86). ADR, adverse drug reaction; ADME, absorption, distribution, metabolism, and excretion; HLA, human leukocyte antigen; pharmacodynamics; pharmacogenomics; PK, pharmacokinetics

Figure 2

Chronology of the pharmacogenomics of severe immunologically mediated adverse drug reactions (ADRs). The discovery of the very strong association between abacavir (ABC) hypersensitivity and the human leukocyte antigen (HLA) B*57:01 gene (HLA‐B*57:01) was the landmark that first linked drug hypersensitivity to class I‐restricted, T cell‐driven mechanisms 18, 19. This discovery set in motion a translational roadmap (right frame) that involved a number of steps that were necessary to confirm the utility, safety and generalizability of HLA‐B*57:01 testing, and resulted in the widespread use of HLA‐B*57:01 testing as a guideline‐based screening test prior to ABC prescription in routine human immunodeficiency virus clinical practice. Since the availability of sequence‐based and deep sequencing methods for high‐resolution typing, there has been a plethora of discoveries over the last 15 years linking severe immune‐modulated ADRs with HLA class I and II alleles. Particularly with severe cutaneous adverse reactions that are CD8+ T cell dependent, such as Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), class I‐restricted HLA associations have dominated. Significant insights into the immunopathogenesis of severe T‐cell‐mediated ADRs have been garnered from these class I‐restricted reactions such as the strong association between carbamazepine SJS/TEN and HLA‐B*15:02 in Southeast Asian populations, and allopurinol severe cutaneous adverse reactions (SCARs) and HLA‐B*58:01. Some additional distinct examples exist, such as the importance of HLA class I/II haplotypes in the setting of amoxicillin–clavulanate (Amox‐clav) drug‐induced liver disease in Northern Europeans and phenotype‐specific HLA associations for nevirapine hypersensitivity 77, 78, 79, 80, 114, 115, 116. More recently, for phenytoin [the cytochrome P450 (CYP) 2C9*3 gene (CYP2C9*3) 73 and nevirapine (CYP2B6 516G > T) SCARs 115, impaired drug metabolism appears to be an important driver. AED, anti‐epileptic drug; DILI, drug‐induced liver disease; DRESS, drug reaction with eosinophilia and systemic symptoms; HSR, hypersensitivity reaction; MPE, maculopapular exanthema; NVP, negative predictive value; RCT, randomized controlled trial