Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis

Abstract

One of the major goals of pharmacogenetics is to elucidate mechanisms and identify patients at increased risk of adverse events (AEs). To date, however, there have been only a few successful examples of this type of approach. In this paper, we describe a retrospective case-control pharmacogenetic study of an AE of unknown mechanism, characterized by elevated levels of serum alanine aminotransferase (ALAT) during long-term treatment with the oral direct thrombin inhibitor ximelagatran. The study was based on 74 cases and 130 treated controls and included both a genome-wide tag single nucleotide polymorphism and large-scale candidate gene analysis. A strong genetic association between elevated ALAT and the MHC alleles DRB1*07 and DQA1*02 was discovered and replicated, suggesting a possible immune pathogenesis. Consistent with this hypothesis, immunological studies suggest that ximelagatran may have the ability to act as a contact sensitizer, and hence be able to stimulate an adaptive immune response.

Rivaroxaban postmarketing risk of liver injury

“…However, liver injury is known under rivaroxaban, labeled adverse reactions include icterus and increased transaminases, alkaline phosphatase, and total and conjugated bilirubin [7]. Of note, the direct thrombin inhibitor ximelagatran was associated with hepatotoxicity during clinical development, which contributed to non-approval by the US FDA, and in other countries marketing was discontinued after serious cases of liver injury associated with ximelagatran appeared in the postmarketing phase [8]. Looking at premarketing data of rivaroxaban, a published evaluation of rivaroxaban's hepatic events in clinical trials was based on its phase III RECORD studies and included 6131 patients exposed to rivaroxaban.…”

Human leukocyte antigen (HLA)-B*57:01-restricted activation of drug-specific T cells provides the immunological basis for flucloxacillin-induced liver injury

“…More recently, histological examination of an inflamed liver from a single patient exposed to sulfasalazine revealed an infiltration of granzyme B secreting T-lymphocytes. 9 The discovery of HLA alleles as risk factors for DILI (e.g., flucloxacillin [B*57:01], 10 ximelagatran [DRB1*07:01], 11 lumiracoxib [DRB1*15:01] 12 ) is supportive of an immune mechanism; however, biological data showing HLA restriction of drug-responsive cytotoxic T cells is lacking. The strength of the association described for flucloxacillin-approximately 85% of cases carry at least one copy of HLA-B*57:01-prompted us to investigate (1) the cellular response in patients with flucloxacillin-induced liver injury, and (2) whether flucloxacillin activates naive CD8þ T cells from HLA-B*57:01-positive volunteers.…”

Mitochondrial and immunoallergic injury increase risk of positive drug rechallenge after drug-induced liver injury: A systematic review

“…Multiple HLA markers have recently been identified which are highly associated with liver injury. [19][20][21][22][23] Hypersensitivity reactions result in rapid onset of rechallenge injury (within hours for some drugs) with accompanying fever, rash, or eosinophilia.…”

“…14,15 The likelihood of DILI is significantly increased in patients exhibiting polymorphisms of mitochondrial DNA polymerase gamma, 16,17 superoxide dismutase 2 (which scavenges mitochondrial superoxide), 18 or specific human leukocyte antigen (HLA) markers associated with immunoallergic injury. [19][20][21][22][23] Immunoallergic injury or hypersensitivity is associated with fever, rash, eosinophilia, and antidrug antibodies and occurs rapidly on rechallenge (sometimes within hours). Immunoallergic injury is initiated when a reactive drug or metabolite binds to intracellular proteins and generates a hapten, which is taken up by antigen-presenting cells and presented with major histocompatibility complex to helper T cells, and further activated by a danger signal of cytokines, such as high mobility group box 1 or other markers of necrosis or inflammation, to stimulate an immune response.…”