Predicted efficacy of a pharmacogenetic passport for inflammatory bowel disease

Abstract

Background: High inter-individual variability in therapeutic response to drugs used in the management of Inflammatory Bowel Disease (IBD) leads to high morbidity and high costs. Genetic variants predictive of thiopurine-induced myelosuppression, thiopurine-induced pancreatitis and immunogenicity of Tumour Necrosis Factor alpha (TNFα) antagonists have been identified, but uptake of pre-treatment pharmacogenetic testing into clinical guidelines has been slow.

Aim: To explore the efficacy of a pharmacogenetic passport for IBD that includes multiple pharmacogenetic predictors of response.

Methods: Patients with IBD exposed to thiopurines and/or TNFα antagonists were retrospectively evaluated for the presence of thiopurine toxicity and/or immunogenicity of TNFα antagonists. All patients were genotyped using both whole-exome sequencing and the Illumina Global Screening Array. An in-house-developed computational pipeline translated genetic data into an IBD pharmacogenetic passport that predicted risks for thiopurine toxicity and immunogenicity of TNFα antagonists per patient. Using pharmacogenetic-guided treatment guidelines, we calculated clinical efficacy estimates for pharmacogenetic testing for IBD.

Results: Among 710 patients with IBD exposed to thiopurines and/or TNFα antagonists, 150 adverse drug responses occurred and our pharmacogenetic passport would have predicted 54 (36%) of these. Using a pharmacogenetic passport for IBD that includes genetic variants predictive of thiopurine-induced myelosuppression, thiopurine-induced pancreatitis, and immunogenicity of TNFα antagonists, 24 patients need to be genotyped to prevent one of these adverse drug responses.

Conclusions: This study highlights the clinical efficacy of a pharmacogenetic passport for IBD. Implementation of such a pharmacogenetic passport into clinical management of IBD may contribute to a reduction in adverse drug responses.

FIGURE 1

Flowchart representing current therapeutic outcomes (past) and proposed pharmacogenetic‐guided treatment strategies (future). Patients defined as candidates for therapy in this figure were exposed to either thiopurines or TNFα antagonists and are hypothesised to be representative of future candidates. Toxicity refers to either thiopurine‐induced myelosuppression or thiopurine‐induced pancreatitis. Antibodies refers to the formation of anti‐drug antibodies to TNFα antagonists, a process referred to as immunogenicity. Patients in red boxes would receive alternative treatment strategies based on pharmacogenetic testing. IBD: inflammatory bowel disease; TNFα: Tumour Necrosis Factor alpha