Applications of Immunopharmacogenomics: Predicting, Preventing, and Understanding Immune-Mediated Adverse Drug Reactions

Abstract

Adverse drug reactions (ADRs) are a significant health care burden. Immune-mediated adverse drug reactions (IM-ADRs) are responsible for one-fifth of ADRs but contribute a disproportionately high amount of that burden due to their severity. Variation in human leukocyte antigen (HLA) genes has emerged as a potential preprescription screening strategy for the prevention of previously unpredictable IM-ADRs. Immunopharmacogenomics combines the disciplines of immunogenomics and pharmacogenomics and focuses on the effects of immune-specific variation on drug disposition and IM-ADRs. In this review, we present the latest evidence for HLA associations with IM-ADRs, ongoing research into biological mechanisms of IM-ADRs, and the translation of clinical actionable biomarkers for IM-ADRs, with a focus on T cell-mediated ADRs. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 59 is January 6, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA‐B Genotypes and Phenytoin Dosing: 2020 Update

“…Furthermore, multiple case studies have observed that CYP2C9 PMs are at increased risk for exposure‐related phenytoin toxicities, and multiple studies have observed an association between the CYP2C9*3 allele and SJS/TEN 25–27 . Although carriage of the CYP2C9*3 allele is insufficient to predict phenytoin‐induced SJS/TEN, these and other data suggest that the risk of SJS/TEN is dose‐related and provide an additional rationale for reducing phenytoin dose in CYP2C9 PMs 28 . Thus, our recommendations are conservative given the variability surrounding phenytoin dosing.…”

“…[25][26][27] Although carriage of the CYP2C9*3 allele is insufficient to predict phenytoin-induced SJS/TEN, these and other data suggest that the risk of SJS/TEN is dose-related and provide an additional rationale for reducing phenytoin dose in CYP2C9 PMs. 28 Thus, our recommendations are conservative given the variability surrounding phenytoin dosing. Based on the doses reported in the pharmacokinetic and pharmacogenetic studies mentioned above [29][30][31] and in Table S2, a typical initial or loading dose followed by at least a 25% reduction in the recommended starting maintenance dose may be considered for CYP2C9 IMs with AS of 1.0.…”

Drug hypersensitivity in HIV infection

“…Genetic predisposition, particularly HLA risk, is important for several delayed IM-ADRs and has been reviewed recently for a number of drugs relevant to HIV, including the antiretrovirals abacavir, nevirapine and certain antiinfectives, for example, dapsone [37]. These genetic risk factors are critical determinants of certain IM-ADRs prior to HIV infection.…”

Genomic Risk Factors Driving Immune-Mediated Delayed Drug Hypersensitivity Reactions

“…(vi) Co-signaling pathways also regulate T-cell activation, with overall co-inhibition or co-stimulation leading to (vii) cytokine release and respective tolerance with T-regulatory cell (Treg)-induced immunosuppression or inflammation and cytotoxic degranulation, respectively. expressed in <1% of patients of European or African ancestry despite global disease burden, restricting universal screening and inferring that different HLA alleles drive reactions in different populations (Karnes et al, 2019). Indeed, multiple alleles are now associated with CBZ-SCAR in distinct populations, with HLA-A * 31:01 associated with DRESS in Europeans and Chinese, but not SJS/TEN (McCormack et al, 2011;Genin et al, 2014), highlighting propensity for distinct alleles to define risk for specific reactions.…”