Human leukocyte antigen and idiosyncratic adverse drug reactions

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54

DMPK149_proof ■ 23 November 2016 ■ 1/10

Drug Metabolism and Pharmacokinetics xxx (2016) 1e10

Contents lists available at ScienceDirect

Drug Metabolism and Pharmacokinetics journal homepage: http://www.journals.elsevier.com/drug-metabolism-andpharmacokinetics

Review

Human leukocyte antigen and idiosyncratic adverse drug reactions Q3

Toru Usui a, Dean J. Naisbitt b, * a

Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan MRC Centre for Drug Safety Science, Department of Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool L69 3GE, England, UK

b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 7 September 2016 Received in revised form 8 November 2016 Accepted 9 November 2016 Available online xxx

A clinical association between a specific human leukocyte antigen (HLA) allele and idiosyncratic adverse drug reactions (IADRs) is a strong indication that IADRs are mediated by the adaptive immune system. For example, it is well-established that HLA-B*15:02 and HLA-B*57:01 are associated with carbamazepine-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and abacavirinduced hypersensitivity/flucloxacillin-induced liver injury, respectively. Drug-specific T-cells whose response is restricted by specific HLA risk alleles have been detected from IADR patients, also suggesting an adaptive immune pathogenesis. T-cells from carbamazepine SJS/TEN patients are activated by direct pharmacological interaction between carbamazepine and HLA-B*15:02 expressed on antigen presenting cells (APCs). Abacavir-specific, HLA-B*57:01-restricted T-cells are activated by APCs presenting peptides which are only displayed by the HLA molecule when abacavir is bound during peptide loading. Finally, HLA-B*57:01-restricted activation of T-cells from patients with flucloxacillin-induced liver injury is dependent on processing of drug protein adducts. Based on these observations, it is now possible to utilize blood from healthy drug-naïve volunteers to study the priming of naïve T-cells to drugs. Future development of these methodologies may lead to the development of assays that predict intrinsic immunogenicity of drugs and chemicals at the preclinical stage of drug development.

Keywords: Hepersensitivity Severe cutaneous adverse reactions Drug-induced liver injury Human leukocyte antigen Reactive metabolites Hapten concept p-i concept Altered peptide repertory concept

© 2016 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

1. Introduction Idiosyncratic adverse drug reactions (IADRs) refer to adverse reactions that do not occur in most patients at any dose of the drug, and typically have a delayed onset of weeks to months after initial exposure [1]. IADRs are a major clinical problem in terms of patient morbidity, mortality, cost to healthcare systems, and failure of drugs in development. The skin and liver are most commonly implicated in IADRs and severe cutaneous adverse reactions (SCARs) and drug-induced liver injury (DILI) are most forms. SCARs particularly Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are serious and life-threatening conditions [2] and

Abbreviations: APC, antigen presenting cell; BB, Bandrowski's base; DILI, druginduced liver injury; GWAS, Genome Wide Association Study; HLA, human leukocyte antigen; IADRs, idiosyncratic adverse drug reactions; MHC, major histocompatibility complex; PBMC, peripheral blood mononuclear cell; p-i, pharmacological interaction; PPD, p-phenylenediamine; SCARs, severe cutaneous adverse reactions; SJS, Stevens-Johnson syndrome; SMX-NO, nitroso sulfamethoxazole; TEN, toxic epidermal necrolysis; TCR, T-cell receptor. * Corresponding author. E-mail address: [email protected] (D.J. Naisbitt).

DILI is the most frequent reason for withdrawal of an approved drug from the market and also a major cause of attrition in drug development [3]. In recent years, retrospective Genome Wide Association Study (GWAS) have identified human leukocyte antigens (HLAs) as an important genetic marker for IADRs, especially for SCARs and for DILI (reviewed in Refs. [4e6]). HLA is necessary for antigen presentation system so the clinical associations provide persuasive evidence to hypothesize that the reactions involve the drug-specific activation of the adaptive immune system. Moreover, mechanistic studies using T-cells from these patients who express risk HLA provide direct evidence to support this [7e9]. Thus, HLA is a promising starting point that must be considered when attempting to develop diagnostic tests that define whether an IADR to a new drug candidate is truly the culprit drug, or to develop pharmacogenetics tests (which might be point of care) for patients to prevent these reactions at clinical stage, or to establish novel in vitro model systems to predict IADRs at preclinical stage. In this review, we summarize recent progress describing clinical HLA associations with IADRs, the latest mechanistic studies using patient samples which link expression of an HLA risk allele to

http://dx.doi.org/10.1016/j.dmpk.2016.11.003 1347-4367/© 2016 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Usui T, Naisbitt DJ, Human leukocyte antigen and idiosyncratic adverse drug reactions, Drug Metabolism and Pharmacokinetics (2016), http://dx.doi.org/10.1016/j.dmpk.2016.11.003

55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

DMPK149_proof ■ 23 November 2016 ■ 2/10

2

T. Usui, D.J. Naisbitt / Drug Metabolism and Pharmacokinetics xxx (2016) 1e10

antigen-specific T-cell activation, and discuss the possibility for developing a predictive tool for IADRs using healthy volunteer samples at the preclinical stage. 2. Clinical association between HLAs and IADRs The HLA system is a gene complex encoding the major histocompatibility complex (MHC) proteins in humans. These cellsurface proteins are responsible for the regulation of the immune system by presenting antigenic peptides to T-cells. The antigen peptide presented by MHC class I (HLA-A, HLA-B, HLA-C) and class II (HLA-DR, HLA-DQ, HLA-DP) are derived from endogenously expressed protein and internalized exogenous protein, and are presented to CD8þ and CD4þ T-cells, respectively. The peptides presented by the HLA are affected by these polymorphisms in multiple ways. Mainly polymorphisms alter the shape and electrochemistry of pockets within the peptide-binding groove that subsequently determine the repertoire of peptides that can bind to a given HLA molecule. Each HLA allotype possesses a specific peptide-binding motif, which can be characterized via sequencing of peptides bound within the cleft [10,11]. Although polymorphism of HLA alleles has been established to drive peptide ligand diversity [12e14], its impact on interactions with small molecule drugs is largely unknown. In the first section of the review we summarize recent clinical associations between HLA molecules and small molecule drug hypersensitivity reactions. 2.1. Clinical association between HLAs and SCARs Since 2001, several IADRs by small molecule drugs have been linked to different HLA alleles (Table 1). Abacavir is a nucleotide analog with antiviral activity against HIV-1. Approximately 5e7% of Caucasian patients develop hypersensitivity within 6 weeks of initial exposure to abacavir [15]. The strong association between the MHC class I allele HLA-B*57:01 and abacavir hypersensitivity was the first association identified and most well studied (odds ratio >900) [15e19]. Preprescription testing for HLA-B*57:01 reduced the frequency of hypersensitivity showing that genetic testing can have a powerful influence in reducing the burden associated with IADRs [20e22].

SCAR is considered to be a delayed-type IADR involving T-cells [23]. Recent reports have implicated the involvement of some HLA class I molecules in the development of drug-induced SCARs. Carbamazepine is widely used in the treatment of epilepsy, trigeminal neuralgia, and bipolar disorder. Carbamazepine- induced SJS/TEN has shown a strong (odds ratio >1000) association with HLA-B*15:02 in the Han Chinese population [24]. This association has also been replicated in several other Asian populations, including Thai [25,26], Malay [27] and Indian subjects [28] but not in white [29e31] and Japanese subjects [32,33]. Significant associations between HLA-B*15:11 and carbamazepine-induced SJS/ TEN have been also found in Japanese patients (OR ¼ 16.3) [34]. HLA-B*15:11 and HLA-B*15:02 belong to the same serotype, HLAB75. The T-cell receptor (TCR) clonotype, Vb-11-ISGSY is dominant for patients with carbamazepine SJS/TEN. Thus assumingly T-cell activation is not only restricted by HLA-B*15:02 but also TCR clonotypes [35]. Interestingly, CBZ-induced SCARs in Caucasian and Japanese populations is associated with HLA-A*31:01 [36,37]. HLA-B*15:02 and HLA-A*31:01 differ greatly in amino acid sequence, however they share two of the three residues suggested to control the interaction of CBZ and HLA-B*15:02 (95Ile and 156Leu but not 63Asn) [9]. It is important to note that this ethnic difference may relate to HLA-B*15:02 allele frequency and does not mean Caucasian/Japanese carriers of HLA-B*15:02 can be safely treated with carbamazepine. Allopurinol is used as a urate-lowering drug and frequently causes SCARs [38]. All Han Chinese and Thai individuals with allopurinol-induced SCAR were found to express HLA-B*58:01. Furthermore, most Korean patients also expressed this allele [38e40]. In all of these populations, the frequency of the HLAB*58:01 allele is high (6.5e10%) [39]. Nonetheless, 45% of patients of European ancestry with allopurinol induced SJS/TEN did not have HLA-B*58:01, suggesting that this allele is not an absolute risk factor [30]. Furthermore, the positive predictive value of HLA-B*58:01 is estimated to be only 2.7%, implying that other risk factors are also important [41]. Associations between other druginduced SCARs and HLA alleles are summarized in Table 1 or reviewed in Refs. [4e6]. Interestingly so far, very strong association between MHC class II allele and SCARs has not been reported.

Table 1 Clinical association between HLAs and IADRs (from representative reports). Drugs

Disease phenotype

HLA association

Odds ratio

Reference

Abacavir Allopurinol Carbamazepine

Hypersensitivity SJS/TEN/DRESS SJS/TEN

Clozapine

Agranulocytosis

Co-amoxicav (amoxicillin- clavulanate)

DILI DILI SJS/TEN DILI Agranulocytosis DILI

>900 50e580 >50e1000 26/33 22 50/23.3 10.7 2.8 2.2 80.6 6.8 2e9

[18,19] [38,149] [26,150,151] [36,37] [53] [55] [54] [46e49]

Flucloxacillin Lamotrigine Lapatinib Levamisole Lumiracoxib

Methazolamide Nevirapine Phenytoin Ticlopidine Ximelagatran

SJS/TEN SCARs SJS/TEN DILI DILI

B*57:01 B*58:01 B*15:02 A*31:01 DRB5*02:01 B*38/DR*4 B*59:01 DRB1*15:01 and DQB1*06:02 A*02:01 B*57:01 B*38 DRB1*07:01, DQA1*02:01, DQB1*02:02 B27 DRB1*15:01 DQB1*06:02 DRB5*01:01 DQA1*01:02 B*59:01 B*35:05 B*15:02 A*33:03 DRB1*07 DQA1*02

7.5 6.9 7.2 6.3 >250 19 18.5 13 4.4 4.4

[42] [30] [50] [56] [51]

[152,153] [154] [25,155] [44] [52]

Please cite this article in press as: Usui T, Naisbitt DJ, Human leukocyte antigen and idiosyncratic adverse drug reactions, Drug Metabolism and Pharmacokinetics (2016), http://dx.doi.org/10.1016/j.dmpk.2016.11.003

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

DMPK149_proof ■ 23 November 2016 ■ 3/10

T. Usui, D.J. Naisbitt / Drug Metabolism and Pharmacokinetics xxx (2016) 1e10

2.2. Clinical association between HLAs and DILI/agranulocytosis Recently several drug-specific associations between DILI and genetic polymorphisms have been reported, particularly with HLA alleles. Flucloxacillin is a semi-synthetic penicillin that is commonly used to treat staphylococcal infection. A strong association between cholestatic hepatitis and expression of HLA-B*57:01 has been described (odds ratio, 80.6) [42]. The anti-platelet drug, ticliopidine is a rare cause of cholestatic type DILI and reactions seem to occur more frequently in the Japanese population [43]. Another MHC class I molecule, HLA-A*33:03 was found to be a significant risk factor (odds ratio, 13) for ticlopidine DILI [44] and the enhanced polymorphism of CYP2B6 which is involved in the formation of S-oxide reactive metabolites of ticlopidine increased the odds ratio, 38 [45]. Several MHC class II molecules have also been identified as significant risk factors for co-amoxiclav [46e49], lapatinib [50], lumiracoxib [51], and ximelagatran [52] induced DILI (listed in Table 1). Some HLA alleles are also a susceptibility factor for drug induced agranulocytosis. HLA-DRB5*02:01, HLA-B*59:01, HLA-B*38/DR*4 and HLA-B27 have been described to be associated with clozapine [53e55] and levamisole [56] induced agranulocytosis, respectively. Pharmacogenomics studies using a GWAS approach and exome sequencing analysis reported clozapine induced agranulocytosis was associated with two independent amino acid changes in HLA-B and HLA-DQB1 [57]. 3. Mechanistic evidence to support a role for the adaptive immune system in IADRs As discussed above, HLA alleles are associated with specific forms of ADR. However, disease phenotypes are also partly dependent on the drug administered. For example, the b-lactam antibiotic flucloxacillin is associated with a high incidence of liver reactions [42], whereas most other b-lactam antibiotics primarily direct the immune system to target the skin. To date there is no data to indicate why drugs of a similar chemical class such as the blactam antibiotics target a particular organ or indeed cause different clinical symptoms in the same organ. The picture is further complicated by the fact that drugs such as flucloxacillin cause skin reactions and even anaphylaxis in certain patients [58,59]. Furthermore, there are drugs such as allopurinol and anticonvulsants, which are the commonest cause of serious skin reactions such as SJS and TEN [24e26,30,36e38]. There is very little mechanistic data [60,61] to indicate why these drugs commonly cause serious reactions, whereas other drugs induce primary milder conditions. For this reason, we now discuss ADR pathogenesis in skin and liver focusing on general mechanisms, further than drug-specific events. 3.1. Pathogenesis e skin The presence of drug-specific T-cells in blood and skin of drughypersensitive patients provides a robust case for the involvement of adaptive immune systems in the pathogenesis of many forms of reaction [62e67]. For instance abacavir-, carbamazepine-, lamotrigine-, and many b-lactam antibiotic-specific T-cells from hypersensitive patients have been detected. These drugspecific T-cell immunophenotypes (CD4/CD8) and cytokine release patterns have been reported. Drug specific CD4þ and CD8þ T-cells that secrete IFN-g/Fas ligand/perforin/granzyme B and display cytotoxicity against autologous target cells have been shown to play a crucial role in the disease pathogenesis (reviewed in Refs. [1,11]). The frequency of CD8þ T-cells that migrate to skin and/or are activated in skin by the drug-derived

3

antigen is often cited as one of the most important factors that determine the severity of the IADR. However, Th1 and Th2 cytokines alongside the more recently described cytokines such as IL-9, -17 and 22 might also determine the nature of the cutaneous immune response and ultimately the severity of tissue injury [68,69]. In carbamazepine-induced SJS/TEN, granulysin released from CD8þ T-cells acts as the significant “killer” and is responsible for the disseminated keratinocyte death [60,61]. Keratinocyte damage in patients with maculopapular reactions to drugs involves CD4þ and CD8þ T-cells, and Th1 and Th2 cytokine secretion is readily detectable [70,71]. Classification of the drugspecific T-cell response in patients with different reactions are largely based on a snapshot of the memory T-cell response detected often many years after the clinical reaction subsides. Thus, future studies are needed to compare the nature of the Tcell response at the time of drug exposure, during the IADR, and in the long term, as patients recover. Meanwhile, a combination of early serum biomarkers (e.g. IL-2 and IFN-g for TEN, Fas ligand and IL-4 for SJS, or IL-17 for drug induced hypersensitivity/drug rash with eosiophila and systemic symptoms, DRESS) may be useful for predicting progression to severe SCARs [72]. Such clinical biomarker is indirect but an implication of adaptive immune mediated pathogenesis for SCARs. 3.2. Pathogenesis - liver The adaptive immune system is often implicated in DILI because it has characteristics, such as a delay in onset and no simple relationship between the dose administered and the risk of liver injury. These features are typical of immune-mediated reactions [1]. In addition, there are several cases with a fast onset upon inadvertent rechallenge and cases associated with fever, rash, and eosinophilic infiltrate in the liver [73]. A case report describing a patient with DRESS has shown that a hypersensitivity reaction can develop into fulminant liver failure [74] and up to 5% of DILI patients suffer SJS/TEN [75]. Histological investigations revealed infiltration of granzyme B-secreting CD3þ lymphocytes in close proximity to apoptotic hepatocytes suggesting that Tlymphocytes participate in the liver reaction [74]. Early studies using the lymphocyte transformation test d a simple in vitro assay based on assessment of lymphocyte proliferative responses in drug-treated and vehicle control cultures d detected drug-specific lymphocyte responses in approximately 50% of patients with DILI [76]. Another study revealed that the lymphocyte transformation test set had a sensitivity (% of DILI patients with a positive lymphocyte transformation test) and specificity (% of control patients with a negative lymphocyte transformation test) of 47.5 and 95.9%, respectively [77]. Flucloxacillin-responsive T-cells have been isolated and fully characterized from patients with DILI. CD8þ clones expressing CeC chemokine receptor, CCR4 and CCR9 migrated towards Chemokine (CeC motif) ligand, CCL17 and CCL25 and secreted IFN-g, perforin, granzyme B and Fas ligand following drug stimulation [8]. Moreover, a liver biopsy from a patient with flucloxacillin-induced liver injury revealed periportal inflammation and the infiltration of cytotoxic CD3þ CD8þ lymphocytes into the liver [78]. Co-amoxicav (amoxicillin-clavulanate), one of the most frequently prescribed antibiotics, is a combination therapy of amoxicillin and clavulanic acid that provides broad-spectrum antimicrobial activity. The clavulanic acid component is believed to increase the risk of DILI by 80 fold [79]. Both amoxicillin- and clavulanic acid-specific CD4þ and CD8þ T-cells have been detected in most DILI patients [80]. These studies define the immune basis for flucloxacillin- and co-amoxicav induced liver injury; however, additional studies are needed to explore the drugspecific T-lymphocyte response in other forms of DILI.

Please cite this article in press as: Usui T, Naisbitt DJ, Human leukocyte antigen and idiosyncratic adverse drug reactions, Drug Metabolism and Pharmacokinetics (2016), http://dx.doi.org/10.1016/j.dmpk.2016.11.003

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

DMPK149_proof ■ 23 November 2016 ■ 4/10

4

T. Usui, D.J. Naisbitt / Drug Metabolism and Pharmacokinetics xxx (2016) 1e10

4. Mechanistic study using patient blood d translational evidence As described above, the association between specific HLA alleles and IADRs provides strong translational evidence that IADRs are mediated by the adaptive immune system. Traditionally however, drugs themselves were thought to be too small to be presented by MHC molecules. Most drugs are much smaller than the peptide ligands of HLA class I (8e12 m) and class II (9e25 m) molecules, and are more comparable in size to 1e3 amino acids [11]. Three nonmutually exclusive models that describe how a small-molecule pharmaceutical might elicit T-cell reactivity have been developed, namely the hapten concept, the pharmacologic interaction (p-i) concept, and the altered peptide repertoire model concept (Fig. 1). Evidence for these concepts obtained from ex vivo analyses of “IADR patient” samples (summarized in Table 2) will be described in this section of the review. 4.1. Hapten concept Hapten formation is believed to be an important step in the generation of drug-specific immune responses. In the hapten concept a reactive metabolite binds covalently to an endogenous protein that then undergoes intracellular processing to generate chemically-modified peptides. These peptides are presented in the context of MHC by antigen presenting cells (APCs) to specific receptors expressed on the surface of T-cells. This concept is transnationally demonstrated by mechanistic studies using blood from patients with a variety of b-lactam antibiotic hypersensitivity reactions (reviewed in Ref. [81]). For example, peripheral blood mononuclear cells (PBMCs) and T-cell clones isolated from piperacillin hypersensitive patients were stimulated when piperacillinalbumin complexes were added to cultures [82]. The fact that these albumin complexes are detected in hypersensitive patients and need to be processed in APC to activate T-cells supports the hapten concept [83,84]. Sulfamethoxazole is a sulfonamide with antimicrobial activity that can cause skin reactions. Sulfamethoxazole is metabolized to nitroso sulfamethoxazole (SMX-NO), which acts as a hapten and activates T-cells via covalent modification of HLA bound peptides and non-HLA associated proteins. However, sulfamethoxazole itself also interacts directly with HLA and/or Tcell receptors to stimulate a T-cell response [64,66,85,86]. Similarly, PBMCs from patients hypersensitive to benzylpenicillin are stimulated by hapten-albumin complexes [87]. Responses to the hapten benzylpenicillenic acid are greater than those to benzylpenicillin, showing the important role played by the precise chemical structure of the hapten [87]. Flucloxacillin was stably presented to T-cells on various HLA molecules. The activation of T-cells was resistant to

Fig. 1. A simple scheme to illustrate how a ternary complex between the drug, MHC molecule, and peptide can be assembled to stimulate a T-cell response [6,11]. The interaction between the peptide and drug can be either covalent (Drug -) or noncovalent (Drug $).

extensive washing and dependent on antigen processing, suggesting a hapten mechanism in certain individuals [8]. Activation of Tcell clones from flucloxacillin-DILI patients was found to be processing-dependent and restricted by HLA-B*57:01 supporting that the hapten concept can be used to describe the drug-specific Tcell response in reactions involving an HLA risk allele. An important point to note is that hapten-protein complexes have been detected in drug tolerant individuals [88]. This clearly shows that the presence of a potential antigen from HLA alone is not sufficient to cause allergy hypersensitivity reaction. 4.2. Pharmacological interaction (p-i) concept An alternative mechanism to describe the interaction of small molecules with immune receptors is the p-i concept. Experiments utilizing cells from patients with carbamazepine SJS/TEN have been used to confirm that a direct “pharmacological” interaction between drug and immune receptors provides a binding energy to stimulate a T-cell proliferative response and cytokine release [9]. The offending drug is postulated to bind noncovalently to TCR or MHC protein in a peptide independent manner to activate Tcells. Carbamazepine presentation to T-cells in the context of HLA-B*15:02 has been shown to occur independent of intracellular drug metabolism or antigen processing but does require MHC-peptide binding to stabilize the peptide-MHC complex on the cell surface [9]. In vitro studies have demonstrated carbamazepine binding to other members of the HLA class I B75 serotype family, suggesting that residues conserved among B75 alleles are involved in the HLA carbamazepine interactions. With regard to HLA-A*31:01, although T-cell activation of a carbamazepine hypersensitivity patient is restricted by HLA-A*31:01 [89,90], no further mechanistic study has been conducted to determine pathway of T-cell activation. Oxypurinol, which is a metabolite of allopurinol, interacts with MHC molecules directly to activate T-cells from hypersensitive patients. The T-cell reaction to oxypurinol in patients with SJS/TEN is restricted by HLAB*58:01. Again the T-cell response does not require intracellular metabolism or processing of a drug-protein adduct [91]. The same mechanism has been reported for oxypurinol-specific T-cells isolated from drug naïve healthy donors who express the risk allele HLA-B*58:01 [92]. 4.3. Altered peptide repertoire concept The final mechanism of drug-specific T-cell activation that has been proposed is referred to as the altered peptide repertoire concept. Importantly, to date this concept only seems to apply to one drug abacavir. The offending drug occupies a position in the peptide-binding groove of the HLA-B*57:01 protein, thereby changing the chemistry of the binding cleft and the peptide specificity for MHC binding. It is proposed that peptides presented in this context are recognized as “foreign” by the immune system and therefore elicit a T-cell response [11,93]. Ex vivo studies have shown that CD8þ T-cells derived from abacavirhypersensitive patients are activated after exposure to abacavirstimulated HLA-B*57:01-expressing APCs [94,95]. Ostrov et al. and Illing et al. [93,96] detected the metabolism-independent, direct, noncovalent, and dose-dependent association of abacavir with amino acids in the HLA-B*57:01 binding cleft. Furthermore, approximately 20%e45% of the peptides eluted from abacavirtreated HLA-B*57:01 expressing APCs were distinct from those recovered from untreated cells, illustrating a dramatic shift in the repertoire of HLA-B*57:01-bound peptide in the presence of abacavir.

Please cite this article in press as: Usui T, Naisbitt DJ, Human leukocyte antigen and idiosyncratic adverse drug reactions, Drug Metabolism and Pharmacokinetics (2016), http://dx.doi.org/10.1016/j.dmpk.2016.11.003

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

DMPK149_proof ■ 23 November 2016 ■ 5/10

T. Usui, D.J. Naisbitt / Drug Metabolism and Pharmacokinetics xxx (2016) 1e10

5

Table 2 The proposed mechanism from patient analysis and T-cell priming detectivity using drug-naïve healthy donors. Drug

DNCB PPD BB Piperacillin Sulfamethoxazole SMX-NO Abacavir

Clinically associated HLA

Ex vivo evidence from patients

Priming result of drug-naïve donors

No association No association

Hapten [106] Hapten [108e111]

No association No association

Hapten [82e84] p-i [64,66,85,86] Hapten [64,66,85,86] Altered peptide [93,96]

PBMC/naïve Naïve/memory Naïve/memory Naïve

B*57:01

Allopurinol Oxypurinol

B*58:01

Carbamazepine

Cell component

Naïve PBMC/naïve

p-i [91]

PBMC PBMC/naïve

B*15:02

p-i [9]

PBMC/naïve

Flucloxacillin

A*31:01 B*57:01

(A*31:01 restricted) [90] Hapten [8]

Naïve PBMC/naïve

Lapatinib Lumiracoxib Ximelagatran

DRB1*07:01 and DQA1*02:01 DRB1*15:01 and DQB1*06:02 DRB1*07:01 and DQA1*02:01

Naïve Naïve Naïve

Risk donor genotyped

Non-genotyped donor Positive [97]/positive [98] Negative [112]/negative [112] Positive [112]/positive [112] Positive [100] Positive [99,100,138]

Positive [7,93,94,113,156]/ negative [100] Positive [92,102] Positive [92,102]/ positive [100] Positive [35,89,100]/ positive [100] Positive [100] Positive [78,101]/ positive [8,100,158] Negative [100] Negative [100] Negative [100]

Negative [91,157] Negative [91,157] or possible to generate clones [92]

Possible to generate clones [101]

5. T-cell or PBMC priming study using T-cell responses to drugs with blood from healthy (non-hypersensitive) donors

tetanus toxoid might be necessary for T-cell priming to drugs that are restricted by MHC class II.

From the view of minimizing IADR risk of a pharmaceutical candidate the ability to detect drug-specific T-cell responses in drug-naïve healthy donors might be useful. The in vitro methodology is referred as a “priming assay” in which the antigen (drug) is cultured with PBMCs or T-cells and autologous irradiated autologous PBMCs or dendritic cells for several days. This is followed by a restimulation step to detect the antigen-specific response [7,97e99]. In this component of the review we discuss the data that has been generated utilizing in vitro priming assays with cells from drug-naïve healthy donors (the findings are summarized in Table 2).

5.2. HLA non associated priming

5.1. HLA restricted T-cell priming The finding that abacavir-specific and HLA-B*57:01-restricted Tcell responses can be detected in PBMC not only in patients with hypersensitivity but also in healthy donors [7] could be a breakthrough for the prediction of IADRs at the preclinical stage. Interestingly, similar responses are not detected with PBMC from HLAB*57:01 negaitive donor blood. These data suggest that HLArestricted reactions can be detected/predicted in T-cell systems using PBMC from healthy donors who express risk HLAs. HLAB*15:02/HLA-A*31:01, HLA-B*57:01, or HLA-B*58:01 healthy carriers also showed a positive priming response against carbamazepine [35,89,100], flucloxacillin [8,78,100,101] and oxpurinol [92,100,102], respectively (Table 2). On the other hand, MHC class II risk HLA carriers did not show T-cell responses to drugs associated with a class II risk allele [100]. Double positive carriers of HLADRB1*07:01 and HLA-DQA1*02:01 are more likely to develop liver marker elevation when exposed to drugs such as ximelagatran [52] or lapatinib [50]. However in vitro T-cell priming has not been detected with these drugs [100]. In vitro priming by lumiracoxib in double positive healthy carriers of HLA-DRB1*15:02 and HLADQB1*06:02 was also not successful against clinical observation [51,100]. Thus, additional method development is required to study MHC-class II restricted T-cell responses in healthy donors. Recently Hirasawa et al. reported lapatinib enhances the binding of peptide derived from tetanus toxoid to HLA-DRB1*07:01 [103]. Thus, it is theoretically possible that peptide from exogenous antigens like

Well-investigated example of translation from in vivo (clinical) sensitization to in vitro “T-cell priming” is 2, 4-dinitrochlorobenzene (DNCB). DNCB induces a type IV hypersensitivity reaction in almost all people exposed to it. Topical DNCB exposure activates a cellular immune response in 100% of subjects that is readily detectable after skin challenge [104,105]. The DNCB-mediated allergic reaction is based on hapten concept because DNCB-responsive T-cell clones which are sensitized clinically proliferate in the presence of the compound via an antigen processing-dependent pathway [106] and dinitrophenyl-modified human serum albumin can be used to prime T-cell responses when processed by dendritic cells [98]. DNCB forms dinitrophenyl-modified protein adducts without metabolism like other dinitrohalobenzenes [107]. Thus, the activation of T-cells in PBMCs from DNCB-naïve donors is detective by priming methods without metabolism [97]. Similarly, allergic contact dermatitis by hair dye component, p-phenylenediamine (PPD), is also based on hapten concept [108e111] and there is no report of clinical association with a risk HLA. PPD is not directly active but is oxidized into an unstable quinonediimine intermediate, which forms dimers, trimers, and ultimately a rearrangement product of the trimer, bandrowski's base (BB). T-cell activation on priming assay can be detectable by BB but not by PPD [112]. No clinical association was reported between specific HLA alleles and piperacillin or sulfamethoxazole skin reactions. Both piperacillin which is reactive spontaneously through the nucleophilic opening of the b-lactam ring and SMX-NO which is a reactive metabolite from sulfamethoxazole showed positive priming of T-cells when the drug antigen is presented in the context of autologous dendritic cells from healthy donors [99,100]. 5.3. Memory T-cell priming Memory T-cells are a subset of infection- or cancer-fighting Tcells that have previously encountered and responded to their cognate antigen (antigen-experienced T-cells). Abacavir activates a memory T-cell population in PBMCs which are primed by abacavir [113] but no response was detected against abacavir in naïve T-cell

Please cite this article in press as: Usui T, Naisbitt DJ, Human leukocyte antigen and idiosyncratic adverse drug reactions, Drug Metabolism and Pharmacokinetics (2016), http://dx.doi.org/10.1016/j.dmpk.2016.11.003

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

DMPK149_proof ■ 23 November 2016 ■ 6/10

6

T. Usui, D.J. Naisbitt / Drug Metabolism and Pharmacokinetics xxx (2016) 1e10

primed by abacavir in another report [100] suggesting abacavir may alter pre-existing peptide-antigen for memory T-cell proliferation. In contrast, primed memory (and naïve) T-cells by BB show a proliferative response and IFN-g secretion after second exposure to BB suggesting that BB-responsive memory T-cells circulate in most healthy donors [112]. Not only volunteers who used hair dye previously but also volunteers who did not use it show lymphocyte proliferation after single ex vivo exposure of BB suggesting that BB may have some danger signaling [114,115]- or non-adaptive(innate immune-) activation potential [110]. In fact, naïve T-cell priming by ximelagatran using volunteer blood who has clinically risk HLA-DRB1*07:01 is negative [100] but ximelagtran activated innate immune factors are detectable [116]. Moreover, as discussed above, lapatinib enhances binding of the ligand peptide derived from tetanus toxoid to HLA-DRB1*07:01 [103]. Taken together, disclosure of the mechanism of memory T-cell priming may also be a key factor for the development of certain forms of drug hypersensitivity; one possible mechanism is stimulation of pre-existing memory T-cell against drug, the other is supportive enhancement of pre-existing memory T-cell reaction against endogenous (MHC class I)/exogenous (MHC class II) antigen via non-adaptive immune mechanism. Further mechanistic studies are strongly desired to investigate the importance of memory T-cell activation by HLA presentation of peptides in the pathogenesis of drug hypersensitivity. 6. Prediction of IADRs based on adaptive immune responses To date, the drug label has been changed for abacavir hypersensitivity and carbamazepine-induced SJS/TEN in Southeast Asians, stating that HLA testing must be performed before commencing the drug [117e119]. Recent recommendations suggest that HLA-B*58:01 screening should be considered before prescribing allopurinol to those from high-risk ancestry, such as Han Chinese or Thai [13,120,121]. Thus, if the risk HLA is clinically and mechanistically robust we might be able to avoid IADRs in clinical use. However the screening is financial and physical burden for patients and the limited use of the drug reduce the drug sales. Furthermore it is very difficult to know the risk HLAs of candidate drug in preclinical or clinical trials. Clinical studies are conducted in limited populations in which the genetic risk allele or alleles associated with such reactions are not prevalent. These reactions are typically recognized a couple of years postmarketing of drugs after significant investment has been made in research and development. Therefore, to know the specific risk HLAs at preclinical stage may a key step to make a go/no go decision during drug development (case 1). On the other hand, when the hypersensitivity reaction is not associated with specific HLAs or is associated with more frequent HLA populations, the reaction may be detected in earlier clinical phase. However, the limited use of the drug in frequent population leads the withdrawal of the candidate (case 2). In fact, even in the oncology therapeutic area, development of the combination of RAF-4 inhibitor vemurafenib, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor ipilimumab has been stopped after a high frequency of serious DILI was reported in a clinical phase I study [122]. 6.1. Prediction based on HLA (case 1) Studies that define the biochemical and structural basis of IADRs are providing assays to detect drug-HLA interactions. An in silico computational docking method which is performed by Auto Dock or ACEdock software can confirm the association between a specific HLA and a specific drug retrospectively [9,57,93]. Yun et al. showed docking data of HLA repertories against oxypurinol or allopurinol

were comparable to clinical onset [92]. An approach by a Japanese group may be more suitable for prospective drug screening because higher risk potential drugs from the cold medicine repertory can be detectable against a specific HLA, i.e., HLA-A*02:06 [123]. The binding affinity between specific HLA and peptides is measurable using the Epivax system [124]. This is based on an ELISA system using a specific HLA antibody. This method needs soluble HLA and peptide and can detect the enhancement or inhibitory effect of drugs within the HLA-peptide complex. However, the inhibitory effect seen with ximelagatran [52] and enhanced effect by lapatinib [103] confuse the situation and provide little information on the underlying mechanism of hypersensitivity. Surface plasmon resonance (SPR) can measure the small molecule binding response to protein as Resonance Units [9,91]. Wei et al. purified HLAs, bmicroglobulin, and endogenous peptide from the culture medium of APCs expressing the risk allele and elegantly showed carbamazepine binds directly to HLA-B*15:02; however, the same was not seen with other HLA-B recombinant proteins [9]. This system should also be applicable for candidate screening against specific HLAs. It is important to point out that these methods are higher throughput than above mentioned PBMC/T-cell priming but cannot evaluate the risk based drugs that activate T-cells via the hapten concept because they often need to be metabolized to bind to proteins [125]. Moreover, knowledge of the HLA molecules the candidate drugs bind to is required. The T-cell priming method discussed above using healthy donor PBMC expressing risk HLAs, especially MHC class I, had the potential to be a powerful prediction tool to evaluate the risk based on both hapten and p-i/altered peptide concepts if risk HLAs are known. On the other hand if the risk is based on MHC class II, it is still unclear whether the assay has the potential to be predictable [100]. 6.2. Prediction of non-HLA restricted forms of hypersensitivity (case 2) When clinical incidence of IADRs is 10% there is a potential to detect by T-cell priming responses by studying as few as 10 healthy donors. Importantly, as discussed above piperacillin- and SMX-NOspecific T-cell responses are detectable in healthy individuals expressing different HLA alleles [99,100]. The detection of T-cell responses in most healthy donors in vitro likely relates to the fact that dendritic cells are matured with LPS and TNFa prior to exposing the drug to T-cells [99]. Taken together, to predict hypersensitivity at preclinical stage, we may need to understand underlying mechanism and select/line up the prediction tool which is based on the mechanisms (summarized in Table 3). 6.3. Animal models Attempts to develop animal models of DILI/SCAR that involve the adaptive immune system have been largely unsuccessful [1,126]; however, in recent years, a few examples have been reported. Shenton et al. [127] reported a rat model of nevirapineinduced skin rash. The reaction has a delayed onset (2e3 weeks), and rechallenge with nevirapine results in the development of clinical symptoms much more rapidly. These phenomena are indicative of an immune-mediated reaction against the drug, and indeed depletion of CD4þ T-cells was found to decrease the incidence of skin rash suggesting that CD4þ T-cells may play a central role in this nevirapine model. On the other hand, C57BL/6 mice with a mutation in the ab gene encoding for MHC class II molecules become sensitized to weak chemical allergens [128,129] or flucloxacillin [130] following epicutaneous application. These data indicate that the CD8þ T-cells are the primary mediators of the reactions in the experimental models.

Please cite this article in press as: Usui T, Naisbitt DJ, Human leukocyte antigen and idiosyncratic adverse drug reactions, Drug Metabolism and Pharmacokinetics (2016), http://dx.doi.org/10.1016/j.dmpk.2016.11.003

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

DMPK149_proof ■ 23 November 2016 ■ 7/10

T. Usui, D.J. Naisbitt / Drug Metabolism and Pharmacokinetics xxx (2016) 1e10

7

Table 3 The availability and scope of application of methods to predict IADRs. Method

Docking Epivax Biacore Priming a b c

Assay system

In silico computational simulation Competition-based HLA-peptide binding assay based on ELISA HLA and small molecule binding affinity assay based on SPR In vitro sensitization system based on Tcell reaction

Mechanistic scope of application

Soluble HLA

Soluble peptide

Throughput

Reference

No No

Not necessary Necessary

Not necessary Necessarya

Middle Middle

[9,57,92,93,123] [52,103,124]

No

No

Necessary

Necessarya,b

High

[9,91]

Evaluable

Evaluable

Not necessary

Not necessaryc

Low

[99,138]

p-i

Altered peptide

Hapten

Evaluable Evaluable

No No

Evaluable Evaluable

Recombinant protein from transfected cell may include endogenous peptides. Affinity between HLA and small molecule might be detectable without peptide when it is based on p-i between HLAs and drugs. When the related HLA is class II exogenous peptide may be needed.

Recent anti-cancer drug, immune check point inhibitor have been shown to break “immune tolerance” which is an immunological signal that prevents activated T-cells from attacking the cancer, thus allowing the immune system to clear the cancer but also induce immune-mediated inflammation. In fact, the combination of nivolumab, which is human program death 1 (PD-1) immune checkpoint inhibitor, and ipilimumab which is another immune check point inhibitor against human CTLA-4 increased the incidence of liver test abnormalities compared to baseline and hepatitis clinically [131e134]. Above described combination of ipilimumab and vemurafenib resulted in synergistic serious liver toxicity in Phase 1 study. This resulted in termination of the trial [122]. The clinical combination risk of nivolumab and ipilimumab was transnationally reproduced by cotreatment of PD-1/ mice with anti-CTLA-4 antibody using amoduaquine [135], isoniazid, or nevirapine [136] resulting in a significant increase in ALT. Depletion of myeloid-derived suppressor cells which are involved in immune tolerance led to an immune response to halothane with liver injury and eosinophilia in mice similar to halothane hepatitis in humans [137]. These tolerance break animal models are promising tool to predict not only DILI but also SCARs and it will be interesting to see whether similar observations are detected with other DILI/SCAR drugs, including those that cause reactions in human patients expressing specific HLA alleles. With regard to in vitro systems, PDL1/PD-1 binding negatively regulates the priming of SMX-NOspecific T-cells [138]. 7. Future perspective In this decade, many pharmaceutical companies have taken the strategy to screen out compounds that form highly reactive metabolites or large covalent binding body burden to avoid DILI/SCARs [139e141]. Cell transition (lipophilicity, logP [142]), bile salt export pump [143], mitochondrial toxicity [144], metabolism mediated cytotoxicity [145] are also useful especially to avoid DILI and recently the strategy is growing to include a physiologically base and mathematical model with mitochondrial dysfunction, bile acid related transporter inhibition, or population pharmacokinetics parameters [146e148]. However, there is a mechanistic omission in these models as the adaptive immune system is excluded from the “avoiding risk strategy”. Reactive metabolite formation may be a risk factor for the hapten concept but cannot cover the risk of p-i drugs. Furthermore risk avoiding system might abandon a lot of pharmacologically valuable candidates in screening stage (There are some false positive drugs in previous report of classification [139,140]). Hence the comprehensive evaluation system based on scientific mechanisms is needed. T-cell priming is powerful tool to predict IADRs based on the adaptive immune system; however, it is still insufficient because of low metabolic activity, the difficulty of

identification of risk HLAs, and low sensitivity especially in MHC class II restricted reactions. Thus, more clinical pharmacogenomic data (not only HLAs) is needed to investigate and understand the underlying mechanisms transnationally, and finally to develop predictive systems including all relevant components.

Conflict of interest No conflict of interest.

References [1] Uetrecht J, Naisbitt DJ. Idiosyncratic adverse drug reactions: current concepts. Pharmacol Rev 2013;65:779e808. [2] Roujeau JC, Kelly JP, Naldi L, Rzany B, Stern RS, Anderson T, et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 1995;333:1600e7. [3] Lee WM. Drug-induced hepatotoxicity. N Engl J Med 2003;349:474e85. [4] Illing PT, Vivian JP, Purcell AW, Rossjohn J, McCluskey J. Human leukocyte antigen-associated drug hypersensitivity. Curr Opin Immunol 2013;25:81e9. [5] Kaniwa N, Saito Y. Pharmacogenomics of severe cutaneous adverse reactions and drug-induced liver injury. J Hum Genet 2013;58:317e26. [6] Pirmohamed M, Ostrov DA, Park BK. New genetic findings lead the way to a better understanding of fundamental mechanisms of drug hypersensitivity. J Allergy Clin Immunol 2015;136:236e44. [7] Chessman D, Kostenko L, Lethborg T, Purcell AW, Williamson NA, Chen Z, et al. Human leukocyte antigen class I-restricted activation of CD8þ T cells provides the immunogenetic basis of a systemic drug hypersensitivity. Immunity 2008;28:822e32. [8] Monshi MM, Faulkner L, Gibson A, Jenkins RE, Farrell J, Earnshaw CJ, et al. Human leukocyte antigen (HLA)-B*57:01-restricted activation of drugspecific T cells provides the immunological basis for flucloxacillin-induced liver injury. Hepatology 2013;57:727e39. [9] Wei CY, Chung WH, Huang HW, Chen YT, Hung SI. Direct interaction between HLA-B and carbamazepine activates T cells in patients with StevensJohnson syndrome. J Allergy Clin Immunol 2012;129:1562e9. e5. [10] Dudek NL, Perlmutter P, Aguilar MI, Croft NP, Purcell AW. Epitope discovery and their use in peptide based vaccines. Curr Pharm Des 2010;16:3149e57. [11] Illing PT, Mifsud NA, Purcell AW. Allotype specific interactions of drugs and HLA molecules in hypersensitivity reactions. Curr Opin Immunol 2016;42: 31e40. [12] Bade-Doding C, Theodossis A, Gras S, Kjer-Nielsen L, Eiz-Vesper B, Seltsam A, et al. The impact of human leukocyte antigen (HLA) micropolymorphism on ligand specificity within the HLA-B*41 allotypic family. Haematologica 2011;96:110e8. [13] Burrows JM, Wynn KK, Tynan FE, Archbold J, Miles JJ, Bell MJ, et al. The impact of HLA-B micropolymorphism outside primary peptide anchor pockets on the CTL response to CMV. Eur J Immunol 2007;37:946e53. [14] Macdonald WA, Purcell AW, Mifsud NA, Ely LK, Williams DS, Chang L, et al. A naturally selected dimorphism within the HLA-B44 supertype alters class I structure, peptide repertoire, and T cell recognition. J Exp Med 2003;198: 679e91. [15] Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002;359: 727e32. [16] Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 2002;359:1121e2.

Please cite this article in press as: Usui T, Naisbitt DJ, Human leukocyte antigen and idiosyncratic adverse drug reactions, Drug Metabolism and Pharmacokinetics (2016), http://dx.doi.org/10.1016/j.dmpk.2016.11.003

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

DMPK149_proof ■ 23 November 2016 ■ 8/10

8

T. Usui, D.J. Naisbitt / Drug Metabolism and Pharmacokinetics xxx (2016) 1e10

[17] Hughes DA, Vilar FJ, Ward CC, Alfirevic A, Park BK, Pirmohamed M. Costeffectiveness analysis of HLA B*5701 genotyping in preventing abacavir hypersensitivity. Pharmacogenetics 2004;14:335e42. [18] Martin AM, Nolan D, Gaudieri S, Almeida CA, Nolan R, James I, et al. Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. Proc Natl Acad Sci U S A 2004;101:4180e5. [19] Saag M, Balu R, Phillips E, Brachman P, Martorell C, Burman W, et al. High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis 2008;46:1111e8. [20] Rauch A, Nolan D, Martin A, McKinnon E, Almeida C, Mallal S. Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV cohort study. Clin Infect Dis 2006;43: 99e102. [21] Waters LJ, Mandalia S, Gazzard B, Nelson M. Prospective HLA-B*5701 screening and abacavir hypersensitivity: a single centre experience. AIDS 2007;21:2533e4. [22] Zucman D, Truchis P, Majerholc C, Stegman S, Caillat-Zucman S. Prospective screening for human leukocyte antigen-B*5701 avoids abacavir hypersensitivity reaction in the ethnically mixed French HIV population. J Acquir Immune Defic Syndr 2007;45:1e3. [23] Torres MJ, Mayorga C, Blanca M. Nonimmediate allergic reactions induced by drugs: pathogenesis and diagnostic tests. J Investig Allergol Clin Immunol 2009;19:80e90. [24] Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature 2004;428:486. [25] Locharernkul C, Loplumlert J, Limotai C, Korkij W, Desudchit T, Tongkobpetch S, et al. Carbamazepine and phenytoin induced StevensJohnson syndrome is associated with HLA-B*1502 allele in Thai population. Epilepsia 2008;49:2087e91. [26] Tassaneeyakul W, Tiamkao S, Jantararoungtong T, Chen P, Lin SY, Chen WH, et al. Association between HLA-B*1502 and carbamazepine-induced severe cutaneous adverse drug reactions in a Thai population. Epilepsia 2010;51: 926e30. [27] Ding WY, Lee CK, Choon SE. Cutaneous adverse drug reactions seen in a tertiary hospital in Johor, Malaysia. Int J Dermatol 2010;49:834e41. [28] Mehta TY, Prajapati LM, Mittal B, Joshi CG, Sheth JJ, Patel DB, et al. Association of HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome among Indians. Indian J Dermatol Venereol Leprol 2009;75: 579e82. [29] Alfirevic A, Jorgensen AL, Williamson PR, Chadwick DW, Park BK, Pirmohamed M. HLA-B locus in Caucasian patients with carbamazepine hypersensitivity. Pharmacogenomics 2006;7:813e8. [30] Lonjou C, Borot N, Sekula P, Ledger N, Thomas L, Halevy S, et al. A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs. Pharmacogenet Genomics 2008;18:99e107. [31] Lonjou C, Thomas L, Borot N, Ledger N, de Toma C, LeLouet H, et al. A marker for Stevens-Johnson syndrome...: ethnicity matters. Pharmacogenomics J 2006;6:265e8. [32] Ikeda H, Takahashi Y, Yamazaki E, Fujiwara T, Kaniwa N, Saito Y, et al. HLA class I markers in Japanese patients with carbamazepine-induced cutaneous adverse reactions. Epilepsia 2010;51:297e300. [33] Kaniwa N, Saito Y, Aihara M, Matsunaga K, Tohkin M, Kurose K, et al. HLA-B locus in Japanese patients with anti-epileptics and allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis. Pharmacogenomics 2008;9:1617e22. [34] Kaniwa N, Saito Y, Aihara M, Matsunaga K, Tohkin M, Kurose K, et al. HLAB*1511 is a risk factor for carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients. Epilepsia 2010;51:2461e5. [35] Ko TM, Chung WH, Wei CY, Shih HY, Chen JK, Lin CH, et al. Shared and restricted T-cell receptor use is crucial for carbamazepine-induced StevensJohnson syndrome. J Allergy Clin Immunol 2011;128:1266e76. e11. [36] McCormack M, Alfirevic A, Bourgeois S, Farrell JJ, Kasperaviciute D, Carrington M, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med 2011;364:1134e43. [37] Ozeki T, Mushiroda T, Yowang A, Takahashi A, Kubo M, Shirakata Y, et al. Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population. Hum Mol Genet 2011;20:1034e41. [38] Hung SI, Chung WH, Liou LB, Chu CC, Lin M, Huang HP, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A 2005;102:4134e9. [39] Kang HR, Jee YK, Kim YS, Lee CH, Jung JW, Kim SH, et al. Positive and negative associations of HLA class I alleles with allopurinol-induced SCARs in Koreans. Pharmacogenet Genomics 2011;21:303e7. [40] Tassaneeyakul W, Jantararoungtong T, Chen P, Lin PY, Tiamkao S, Khunarkornsiri U, et al. Strong association between HLA-B*5801 and allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a Thai population. Pharmacogenet Genomics 2009;19:704e9. [41] Phillips EJ, Mallal SA. Pharmacogenetics of drug hypersensitivity. Pharmacogenomics 2010;11:973e87. [42] Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Pe'er I, Floratos A, et al. HLAB*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 2009;41:816e9.

[43] Mizushima M, Iwata N, Fujimoto TT, Ishikawa K, Fujimura K. Patient characteristics in ticlopidine hydrochloride-induced liver injury: case-control study. Hepatol Res 2005;33:234e40. [44] Hirata K, Takagi H, Yamamoto M, Matsumoto T, Nishiya T, Mori K, et al. Ticlopidine-induced hepatotoxicity is associated with specific human leukocyte antigen genomic subtypes in Japanese patients: a preliminary case-control study. Pharmacogenomics J 2008;8:29e33. [45] Ariyoshi N, Iga Y, Hirata K, Sato Y, Miura G, Ishii I, et al. Enhanced susceptibility of HLA-mediated ticlopidine-induced idiosyncratic hepatotoxicity by CYP2B6 polymorphism in Japanese. Drug Metab Pharmacokinet 2010;25:298e306. [46] Donaldson PT, Daly AK, Henderson J, Graham J, Pirmohamed M, Bernal W, et al. Human leucocyte antigen class II genotype in susceptibility and resistance to co-amoxiclav-induced liver injury. J Hepatol 2010;53:1049e53. [47] Hautekeete ML, Horsmans Y, Van Waeyenberge C, Demanet C, Henrion J, Verbist L, et al. HLA association of amoxicillin-clavulanateeinduced hepatitis. Gastroenterology 1999;117:1181e6. [48] Lucena MI, Molokhia M, Shen Y, Urban TJ, Aithal GP, Andrade RJ, et al. Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles. Gastroenterology 2011;141:338e47. [49] O'Donohue J, Oien KA, Donaldson P, Underhill J, Clare M, MacSween RN, et al. Co-amoxiclav jaundice: clinical and histological features and HLA class II association. Gut 2000;47:717e20. [50] Spraggs CF, Budde LR, Briley LP, Bing N, Cox CJ, King KS, et al. HLA-DQA1*02: 01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. J Clin Oncol 2011;29:667e73. [51] Singer JB, Lewitzky S, Leroy E, Yang F, Zhao X, Klickstein L, et al. A genomewide study identifies HLA alleles associated with lumiracoxib-related liver injury. Nat Genet 2010;42:711e4. [52] Kindmark A, Jawaid A, Harbron CG, Barratt BJ, Bengtsson OF, Andersson TB, et al. Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. Pharmacogenomics J 2008;8:186e95. [53] Dettling M, Cascorbi I, Opgen-Rhein C, Schaub R. Clozapine-induced agranulocytosis in schizophrenic Caucasians: confirming clues for associations with human leukocyte class I and II antigens. Pharmacogenomics J 2007;7:325e32. [54] Saito T, Ikeda M, Mushiroda T, Ozeki T, Kondo K, Shimasaki A, et al. Pharmacogenomic study of clozapine-induced agranulocytosis/granulocytopenia in a Japanese population. Biol Psychiatry 2016. Q1 [55] Yunis JJ, Corzo D, Salazar M, Lieberman JA, Howard A, Yunis EJ. HLA associations in clozapine-induced agranulocytosis. Blood 1995;86:1177e83. [56] Schmidt KL, Mueller-Eckhardt C. Agranulocytosis, levamisole, and HLA-B27. Lancet 1977;2:85. [57] Goldstein JI, Jarskog LF, Hilliard C, Alfirevic A, Duncan L, Fourches D, et al. Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles. Nat Commun 2014;5:4757. [58] Almqvist C, Wettermark B, Hedlin G, Ye W, Lundholm C. Antibiotics and asthma medication in a large register-based cohort study - confounding, cause and effect. Clin Exp Allergy 2012;42:104e11. [59] Fleming JD, Fogo AJ, Creamer DJ. Stevens-Johnson syndrome triggered by seasonal influenza vaccination and flucloxacillin: a pathogenetic hypothesis. Eur J Dermatol 2011;21:434e5. [60] Chung WH, Hung SI, Yang JY, Su SC, Huang SP, Wei CY, et al. Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. Nat Med 2008;14:1343e50. [61] Wang CW, Chung WH, Cheng YF, Ying NW, Peck K, Chen YT, et al. A new nucleic acid-based agent inhibits cytotoxic T lymphocyte-mediated immune disorders. J Allergy Clin Immunol 2013;132:713e22. e11. [62] Beeler A, Engler O, Gerber BO, Pichler WJ. Long-lasting reactivity and high frequency of drug-specific T cells after severe systemic drug hypersensitivity reactions. J Allergy Clin Immunol 2006;117:455e62. [63] Brander C, Mauri-Hellweg D, Bettens F, Rolli H, Goldman M, Pichler WJ. Heterogeneous T cell responses to beta-lactam-modified self-structures are observed in penicillin-allergic individuals. J Immunol 1995;155:2670e8. [64] Castrejon JL, Berry N, El-Ghaiesh S, Gerber B, Pichler WJ, Park BK, et al. Stimulation of human T cells with sulfonamides and sulfonamide metabolites. J Allergy Clin Immunol 2010;125:411e8. e4. [65] Nassif A, Bensussan A, Boumsell L, Deniaud A, Moslehi H, Wolkenstein P, et al. Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells. J Allergy Clin Immunol 2004;114:1209e15. [66] Schnyder B, Burkhart C, Schnyder-Frutig K, von Greyerz S, Naisbitt DJ, Pirmohamed M, et al. Recognition of sulfamethoxazole and its reactive metabolites by drug-specific CD4þ T cells from allergic individuals. J Immunol 2000;164:6647e54. [67] Wu Y, Farrell J, Pirmohamed M, Park BK, Naisbitt DJ. Generation and characterization of antigen-specific CD4þ, CD8þ, and CD4þCD8þ T-cell clones from patients with carbamazepine hypersensitivity. J Allergy Clin Immunol 2007;119:973e81. [68] Eyerich S, Eyerich K, Cavani A, Schmidt-Weber C. IL-17 and IL-22: siblings, not twins. Trends Immunol 2010;31:354e61. [69] Pennino D, Eyerich K, Scarponi C, Carbone T, Eyerich S, Nasorri F, et al. IL-17 amplifies human contact hypersensitivity by licensing hapten nonspecific Th1 cells to kill autologous keratinocytes. J Immunol 2010;184:4880e8. [70] Kuechler PC, Britschgi M, Schmid S, Hari Y, Grabscheid B, Pichler WJ. Cytotoxic mechanisms in different forms of T-cell-mediated drug allergies. Allergy 2004;59:613e22.

Please cite this article in press as: Usui T, Naisbitt DJ, Human leukocyte antigen and idiosyncratic adverse drug reactions, Drug Metabolism and Pharmacokinetics (2016), http://dx.doi.org/10.1016/j.dmpk.2016.11.003

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

DMPK149_proof ■ 23 November 2016 ■ 9/10

T. Usui, D.J. Naisbitt / Drug Metabolism and Pharmacokinetics xxx (2016) 1e10 [71] Rozieres A, Hennino A, Rodet K, Gutowski MC, Gunera-Saad N, Berard F, et al. Detection and quantification of drug-specific T cells in penicillin allergy. Allergy 2009;64:534e42. [72] Shiohara T, Mizukawa Y, Aoyama Y. Monitoring the acute response in severe hypersensitivity reactions to drugs. Curr Opin Allergy Clin Immunol 2015;15: 294e9. [73] Maddrey WC, Boitnott JK. Isoniazid hepatitis. Ann Intern Med 1973;79:1e12. [74] Mennicke M, Zawodniak A, Keller M, Wilkens L, Yawalkar N, Stickel F, et al. Fulminant liver failure after vancomycin in a sulfasalazine-induced DRESS syndrome: fatal recurrence after liver transplantation. Am J Transpl 2009;9: 2197e202. [75] Devarbhavi H, Raj S, Aradya VH, Rangegowda VT, Veeranna GP, Singh R, et al. Drug-induced liver injury associated with Stevens-Johnson syndrome/toxic epidermal necrolysis: patient characteristics, causes, and outcome in 36 cases. Hepatology 2016;63:993e9. [76] Maria VA, Victorino RM. Diagnostic value of specific T cell reactivity to drugs in 95 cases of drug induced liver injury. Gut 1997;41:534e40. [77] Chen GY, Chen CW, Fu QC, Wang XJ, Ni LD, Jiang XH, et al. [Set up drug lymphocyte stimulation test (3H-TdR) and observe its application in druginduced liver injury]. Zhonghua Gan Zang Bing Za Zhi 2012;20:190e2. [78] Wuillemin N, Terracciano L, Beltraminelli H, Schlapbach C, Fontana S, Krahenbuhl S, et al. T cells infiltrate the liver and kill hepatocytes in HLA-B( *)57:01-associated floxacillin-induced liver injury. Am J Pathol 2014;184: 1677e82. [79] de Abajo FJ, Montero D, Madurga M, Garcia Rodriguez LA. Acute and clinically relevant drug-induced liver injury: a population based case-control study. Br J Clin Pharmacol 2004;58:71e80. [80] Kim SH, Saide K, Farrell J, Faulkner L, Tailor A, Ogese M, et al. Characterization of amoxicillin- and clavulanic acid-specific T cells in patients with amoxicillin-clavulanate-induced liver injury. Hepatology 2015;62:887e99. [81] Faulkner L, Meng X, Park BK, Naisbitt DJ. The importance of hapten-protein complex formation in the development of drug allergy. Curr Opin Allergy Clin Immunol 2014;14:293e300. [82] Jenkins RE, Yaseen FS, Monshi MM, Whitaker P, Meng X, Farrell J, et al. betaLactam antibiotics form distinct haptenic structures on albumin and activate drug-specific T-lymphocyte responses in multiallergic patients with cystic fibrosis. Chem Res Toxicol 2013;26:963e75. [83] El-Ghaiesh S, Monshi MM, Whitaker P, Jenkins R, Meng X, Farrell J, et al. Characterization of the antigen specificity of T-cell clones from piperacillinhypersensitive patients with cystic fibrosis. J Pharmacol Exp Ther 2012;341: 597e610. [84] Whitaker P, Meng X, Lavergne SN, El-Ghaiesh S, Monshi M, Earnshaw C, et al. Mass spectrometric characterization of circulating and functional antigens derived from piperacillin in patients with cystic fibrosis. J Immunol 2011;187:200e11. [85] Burkhart C, von Greyerz S, Depta JP, Naisbitt DJ, Britschgi M, Park KB, et al. Influence of reduced glutathione on the proliferative response of sulfamethoxazole-specific and sulfamethoxazole-metabolite-specific human CD4þ T-cells. Br J Pharmacol 2001;132:623e30. [86] Elsheikh A, Castrejon L, Lavergne SN, Whitaker P, Monshi M, Callan H, et al. Enhanced antigenicity leads to altered immunogenicity in sulfamethoxazolehypersensitive patients with cystic fibrosis. J Allergy Clin Immunol 2011;127:1543e51. e3. [87] Meng X, Jenkins RE, Berry NG, Maggs JL, Farrell J, Lane CS, et al. Direct evidence for the formation of diastereoisomeric benzylpenicilloyl haptens from benzylpenicillin and benzylpenicillenic acid in patients. J Pharmacol Exp Ther 2011;338:841e9. [88] Jenkins RE, Meng X, Elliott VL, Kitteringham NR, Pirmohamed M, Park BK. Characterisation of flucloxacillin and 5-hydroxymethyl flucloxacillin haptenated HSA in vitro and in vivo. Proteomics Clin Appl 2009;3:720e9. [89] Farrell J, Lichtenfels M, Sullivan A, Elliott EC, Alfirevic A, Stachulski AV, et al. Activation of carbamazepine-responsive T-cell clones with metabolically inert halogenated derivatives. J Allergy Clin Immunol 2013;132:493e5. [90] Lichtenfels M, Farrell J, Ogese MO, Bell CC, Eckle S, McCluskey J, et al. HLA restriction of carbamazepine-specific T-Cell clones from an HLA-A*31:01positive hypersensitive patient. Chem Res Toxicol 2014;27:175e7. [91] Lin CH, Chen JK, Ko TM, Wei CY, Wu JY, Chung WH, et al. Immunologic basis for allopurinol-induced severe cutaneous adverse reactions: HLA-B*58:01restricted activation of drug-specific T cells and molecular interaction. J Allergy Clin Immunol 2015;135:1063e5. e5. [92] Yun J, Marcaida MJ, Eriksson KK, Jamin H, Fontana S, Pichler WJ, et al. Oxypurinol directly and immediately activates the drug-specific T cells via the preferential use of HLA-B*58:01. J Immunol 2014;192:2984e93. [93] Illing PT, Vivian JP, Dudek NL, Kostenko L, Chen Z, Bharadwaj M, et al. Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Nature 2012;486:554e8. [94] Adam J, Eriksson KK, Schnyder B, Fontana S, Pichler WJ, Yerly D. Avidity determines T-cell reactivity in abacavir hypersensitivity. Eur J Immunol 2012;42:1706e16. [95] Phillips EJ, Wong GA, Kaul R, Shahabi K, Nolan DA, Knowles SR, et al. Clinical and immunogenetic correlates of abacavir hypersensitivity. AIDS 2005;19: 979e81. [96] Ostrov DA, Grant BJ, Pompeu YA, Sidney J, Harndahl M, Southwood S, et al. Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire. Proc Natl Acad Sci U S A 2012;109:9959e64.

9

[97] Dai R, Streilein JW. Naive, hapten-specific human T lymphocytes are primed in vitro with derivatized blood mononuclear cells. J Invest Dermatol 1998;110:29e33. [98] Dietz L, Esser PR, Schmucker SS, Goette I, Richter A, Schnolzer M, et al. Tracking human contact allergens: from mass spectrometric identification of peptide-bound reactive small chemicals to chemical-specific naive human Tcell priming. Toxicol Sci 2010;117:336e47. [99] Faulkner L, Martinsson K, Santoyo-Castelazo A, Cederbrant K, SchuppeKoistinen I, Powell H, et al. The development of in vitro culture methods to characterize primary T-cell responses to drugs. Toxicol Sci 2012;127:150e8. [100] Faulkner L, Gibson A, Sullivan A, Tailor A, Usui T, Alfirevic A, et al. Detection of primary T cell responses to drugs and chemicals in HLA-typed volunteers: implications for the prediction of drug immunogenicity. Toxicol Sci; in press. Q2 [101] Wuillemin N, Adam J, Fontana S, Krahenbuhl S, Pichler WJ, Yerly D. HLA haplotype determines hapten or p-i T cell reactivity to flucloxacillin. J Immunol 2013;190:4956e64. [102] Yun J, Mattsson J, Schnyder K, Fontana S, Largiader CR, Pichler WJ, et al. Allopurinol hypersensitivity is primarily mediated by dose-dependent oxypurinol-specific T cell response. Clin Exp Allergy 2013;43:1246e55. [103] Hirasawa M, Hagihara K, Okudaira N, Izumi T. The possible mechanism of idiosyncratic lapatinib-induced liver injury in patients carrying human leukocyte antigen-DRB1*07:01. PLoS One 2015;10:e0130928. [104] Friedmann PS, Moss C, Shuster S, Simpson JM. Quantitative relationships between sensitizing dose of DNCB and reactivity in normal subjects. Clin Exp Immunol 1983;53:709e15. [105] Pickard C, Louafi F, McGuire C, Lowings K, Kumar P, Cooper H, et al. The cutaneous biochemical redox barrier: a component of the innate immune defenses against sensitization by highly reactive environmental xenobiotics. J Immunol 2009;183:7576e84. [106] Pickard C, Smith AM, Cooper H, Strickland I, Jackson J, Healy E, et al. Investigation of mechanisms underlying the T-cell response to the hapten 2,4dinitrochlorobenzene. J Invest Dermatol 2007;127:630e7. [107] Maggs JL, Kitteringham NR, Grabowski PS, Park BK. Drug-protein conjugateseX. The role of protein conjugation in the disposition of dinitrofluorobenzene. Biochem Pharmacol 1986;35:505e13. [108] Bonefeld CM, Larsen JM, Dabelsteen S, Geisler C, White IR, Menne T, et al. Consumer available permanent hair dye products cause major allergic immune activation in an animal model. Br J Dermatol 2010;162:102e7. [109] Coulter EM, Farrell J, Mathews KL, Maggs JL, Pease CK, Lockley DJ, et al. Activation of human dendritic cells by p-phenylenediamine. J Pharmacol Exp Ther 2007;320:885e92. [110] Coulter EM, Jenkinson C, Wu Y, Farrell J, Foster B, Smith A, et al. Activation of T-cells from allergic patients and volunteers by p-phenylenediamine and Bandrowski's base. J Invest Dermatol 2008;128:897e905. [111] Jenkinson C, Jenkins RE, Aleksic M, Pirmohamed M, Naisbitt DJ, Park BK. Characterization of p-phenylenediamine-albumin binding sites and T-cell responses to hapten-modified protein. J Invest Dermatol 2010;130:732e42. [112] Gibson A, Kim SH, Faulkner L, Evely J, Pirmohamed M, Park KB, et al. Vitro priming of naive T-cells with p-phenylenediamine and Bandrowski's base. Chem Res Toxicol 2015;28:2069e77. [113] Lucas A, Lucas M, Strhyn A, Keane NM, McKinnon E, Pavlos R, et al. Abacavirreactive memory T cells are present in drug naive individuals. PLoS One 2015;10:e0117160. [114] Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol 1994;12:991e1045. [115] Zhang X, Sharma AM, Uetrecht J. Identification of danger signals in nevirapine-induced skin rash. Chem Res Toxicol 2013;26:1378e83. [116] Edling Y, Sivertsson L, Andersson TB, Porsmyr-Palmertz M, IngelmanSundberg M. Pro-inflammatory response and adverse drug reactions: mechanisms of action of ximelagatran on chemokine and cytokine activation in a monocyte in vitro model. Toxicol. Vitro 2008;22:1588e94. [117] Kapoor R, Martinez-Vega R, Dong D, Tan SY, Leo YS, Lee CC, et al. Reducing hypersensitivity reactions with HLA-B*5701 genotyping before abacavir prescription: clinically useful but is it cost-effective in Singapore? Pharmacogenet Genomics 2015;25:60e72. [118] Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, et al. HLAB*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008;358: 568e79. [119] Pirmohamed M. Genetics and the potential for predictive tests in adverse drug reactions. Chem Immunol Allergy 2012;97:18e31. [120] Hershfield MS, Callaghan JT, Tassaneeyakul W, Mushiroda T, Thorn CF, Klein TE, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing. Clin Pharmacol Ther 2013;93:153e8. [121] Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken) 2012;64:1431e46. [122] Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med 2013;368: 1365e6. [123] Isogai H, Miyadera H, Ueta M, Sotozono C, Kinoshita S, Tokunaga K, et al. Silico risk assessment of HLA-A*02:06-associated Stevens-Johnson syndrome and toxic epidermal necrolysis caused by cold medicine ingredients. J Toxicol 2013;2013:514068.

Please cite this article in press as: Usui T, Naisbitt DJ, Human leukocyte antigen and idiosyncratic adverse drug reactions, Drug Metabolism and Pharmacokinetics (2016), http://dx.doi.org/10.1016/j.dmpk.2016.11.003

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46

DMPK149_proof ■ 23 November 2016 ■ 10/10

10

T. Usui, D.J. Naisbitt / Drug Metabolism and Pharmacokinetics xxx (2016) 1e10

[124] Steere AC, Klitz W, Drouin EE, Falk BA, Kwok WW, Nepom GT, et al. Antibiotic-refractory Lyme arthritis is associated with HLA-DR molecules that bind a Borrelia burgdorferi peptide. J Exp Med 2006;203:961e71. [125] Sullivan A, Gibson A, Park BK, Naisbitt DJ. Are drug metabolites able to cause T-cell-mediated hypersensitivity reactions? Expert Opin Drug Metab Toxicol 2015;11:357e68. [126] Ju C, Reilly T. Role of immune reactions in drug-induced liver injury (DILI). Drug Metab Rev 2012;44:107e15. [127] Shenton JM, Teranishi M, Abu-Asab MS, Yager JA, Uetrecht JP. Characterization of a potential animal model of an idiosyncratic drug reaction: nevirapine-induced skin rash in the rat. Chem Res Toxicol 2003;16:1078e89. [128] Vocanson M, Hennino A, Cluzel-Tailhardat M, Saint-Mezard P, Benetiere J, Chavagnac C, et al. CD8þ T cells are effector cells of contact dermatitis to common skin allergens in mice. J Invest Dermatol 2006;126:815e20. [129] Vocanson M, Hennino A, Rozieres A, Cluzel-Tailhardat M, Poyet G, Valeyrie M, et al. Skin exposure to weak and moderate contact allergens induces IFNgamma production by lymph node cells of CD4þ T-cell-depleted mice. J Invest Dermatol 2009;129:1185e91. [130] Nattrass R, Faulkner L, Vocanson M, Antoine DJ, Kipar A, Kenna G, et al. Activation of flucloxacillin-specific CD8þ T-cells with the potential to promote hepatocyte cytotoxicity in a mouse model. Toxicol Sci 2015;146: 146e56. [131] Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol 2015;16:522e30. [132] Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015;373:23e34. [133] Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015;372:320e30. [134] Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015;16:375e84. [135] Metushi IG, Hayes MA, Uetrecht J. Treatment of PD-1(-/-) mice with amodiaquine and anti-CTLA4 leads to liver injury similar to idiosyncratic liver injury in patients. Hepatology 2015;61:1332e42. [136] Mak A, Uetrecht J. The combination of anti-CTLA-4 and PD1-/- mice unmasks the potential of isoniazid and nevirapine to cause liver injury. Chem Res Toxicol 2015;28:2287e91. [137] Chakraborty M, Fullerton AM, Semple K, Chea LS, Proctor WR, Bourdi M, et al. Drug-induced allergic hepatitis develops in mice when myeloid-derived suppressor cells are depleted prior to halothane treatment. Hepatology 2015;62:546e57. [138] Gibson A, Ogese M, Sullivan A, Wang E, Saide K, Whitaker P, et al. Negative regulation by PD-L1 during drug-specific priming of IL-22-secreting T cells and the influence of PD-1 on effector T cell function. J Immunol 2014;192: 2611e21. [139] Nakayama S, Atsumi R, Takakusa H, Kobayashi Y, Kurihara A, Nagai Y, et al. A zone classification system for risk assessment of idiosyncratic drug toxicity using daily dose and covalent binding. Drug Metab Dispos 2009;37:1970e7. [140] Thompson RA, Isin EM, Li Y, Weidolf L, Page K, Wilson I, et al. In vitro approach to assess the potential for risk of idiosyncratic adverse reactions caused by candidate drugs. Chem Res Toxicol 2012;25:1616e32. [141] Usui T, Mise M, Hashizume T, Yabuki M, Komuro S. Evaluation of the potential for drug-induced liver injury based on in vitro covalent binding to human liver proteins. Drug Metab Dispos 2009;37:2383e92.

[142] Chen M, Borlak J, Tong WA. Model to predict severity of drug-induced liver injury in humans. Hepatology 2016. [143] Dawson S, Stahl S, Paul N, Barber J, Kenna JG. In vitro inhibition of the bile salt export pump correlates with risk of cholestatic drug-induced liver injury in humans. Drug Metab Dispos 2012;40:130e8. [144] Xu JJ, Henstock PV, Dunn MC, Smith AR, Chabot JR, de Graaf D. Cellular imaging predictions of clinical drug-induced liver injury. Toxicol Sci 2008;105:97e105. [145] Greer ML, Barber J, Eakins J, Kenna JG. Cell based approaches for evaluation of drug-induced liver injury. Toxicology 2010;268:125e31. [146] Howell BA, Yang Y, Kumar R, Woodhead JL, Harrill AH, Clewell 3rd HJ, et al. In vitro to in vivo extrapolation and species response comparisons for druginduced liver injury (DILI) using DILIsym: a mechanistic, mathematical model of DILI. J Pharmacokinet Pharmacodyn 2012;39:527e41. [147] Longo DM, Yang Y, Watkins PB, Howell BA, Siler SQ. Elucidating differences in the hepatotoxic potential of Tolcapone and entacapone with DILIsym((R)), a mechanistic model of drug-induced liver injury. CPT Pharmacometrics Syst Pharmacol 2016;5:31e9. [148] Yang K, Woodhead JL, Watkins PB, Howell BA, Brouwer KL. Systems pharmacology modeling predicts delayed presentation and species differences in bile acid-mediated troglitazone hepatotoxicity. Clin Pharmacol Ther 2014;96:589e98. [149] Ng CY, Yeh YT, Wang CW, Hung SI, Yang CH, Chang YC, et al. Impact of the HLA-B(*)58:01 allele and Renal impairment on allopurinol-induced cutaneous adverse reactions. J Invest Dermatol 2016;136:1373e81. [150] Hung SI, Chung WH, Jee SH, Chen WC, Chang YT, Lee WR, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics 2006;16:297e306. [151] Wang Q, Zhou JQ, Zhou LM, Chen ZY, Fang ZY, Chen SD, et al. Association between HLA-B*1502 allele and carbamazepine-induced severe cutaneous adverse reactions in Han people of southern China mainland. Seizure 2011;20:446e8. [152] Kim SH, Kim M, Lee KW, Kang HR, Park HW, Jee YK. HLA-B*5901 is strongly associated with methazolamide-induced Stevens-Johnson syndrome/toxic epidermal necrolysis. Pharmacogenomics 2010;11:879e84. [153] Yang F, Xuan J, Chen J, Zhong H, Luo H, Zhou P, et al. HLA-B*59:01: a marker for Stevens-Johnson syndrome/toxic epidermal necrolysis caused by methazolamide in Han Chinese. Pharmacogenomics J 2016;16:83e7. [154] Chantarangsu S, Mushiroda T, Mahasirimongkol S, Kiertiburanakul S, Sungkanuparph S, Manosuthi W, et al. HLA-B*3505 allele is a strong predictor for nevirapine-induced skin adverse drug reactions in HIV-infected Thai patients. Pharmacogenet Genomics 2009;19:139e46. [155] Man CB, Kwan P, Baum L, Yu E, Lau KM, Cheng AS, et al. Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese. Epilepsia 2007;48:1015e8. [156] Bell CC, Faulkner L, Martinsson K, Farrell J, Alfirevic A, Tugwood J, et al. Tcells from HLA-B*57:01þ human subjects are activated with abacavir through two independent pathways and induce cell death by multiple mechanisms. Chem Res Toxicol 2013;26:759e66. [157] Chung WH, Pan RY, Chu MT, Chin SW, Huang YL, Wang WC, et al. Oxypurinol-specific T cells possess preferential TCR clonotypes and express granulysin in allopurinol-induced severe cutaneous adverse reactions. J Invest Dermatol 2015;135:2237e48. [158] Yaseen FS, Saide K, Kim SH, Monshi M, Tailor A, Wood S, et al. Promiscuous T-cell responses to drugs and drug-haptens. J Allergy Clin Immunol 2015;136:474e6. e8.

Please cite this article in press as: Usui T, Naisbitt DJ, Human leukocyte antigen and idiosyncratic adverse drug reactions, Drug Metabolism and Pharmacokinetics (2016), http://dx.doi.org/10.1016/j.dmpk.2016.11.003

47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92