Pharmacogenomics of NAT2 and ABCG2 influence the toxicity and efficacy of sulphasalazine containing DMARD regimens in early rheumatoid arthritis

Abstract

Sulphasalazine (SSA) is a disease modifying anti-rheumatic drug (DMARD) that is commonly used to treat rheumatoid arthritis (RA). Plasma levels of SSA and its metabolite sulphapyridine are influenced by common polymorphisms in genes that encode N-acetyl transferase 2 (NAT2) and ATP-binding cassette protein G2 (ABCG2). Study participants had early RA that was treated with a combination DMARD regimen that included SSA. Toxicity was defined by cessation of SSA due to adverse effects and response as remission after 12 months of treatment. The effect of variables on toxicity was assessed by a Cox-proportional Hazard model and response by logistic regression. After correction for conventional variables, toxicity in 229 participants was influenced by NAT2 phenotype (hazard ratio=1.74 (95% confidence interval (CI) 1.01-3.21), P=0.044) and remission in 141 participants was associated with ABCG2 genotype (odds ratio=3.34 (95% CI 1.18-9.50), P=0.024). In our sample of early RA patients who were primarily treated with a combination of DMARDs, common variants in genes that encode NAT2 and ABCG2 were associated respectively with toxicity and response to SSA.

Phase I study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non‐small‐cell lung cancer

“…Two of three patients experienced anorexia of grade 3 as a DLT at dose level 3 (4.5 g/day), despite adequate prophylactic treatment with anti‐emetic agents. The common adverse events of SASP are gastrointestinal toxicity (nausea, vomiting, gastrointestinal upset, diarrhea, and stomach cramps), fatigue, and headache . It is possible that the observed anorexia reflected synergistic toxicity for the combination of SASP and CDDP.…”

Identification of Febuxostat as a New Strong ABCG2 Inhibitor: Potential Applications and Risks in Clinical Situations

“…In the small intestine, ABCG2 is involved in the efflux of its substrates from the epithelial cells into the intestinal lumen, which could lower their bioavailability. For instance, the plasma concentrations (Yamasaki et al, 2008) and efficacy (Wiese et al, 2014) of orally administered sulfasalazine, an antirheumatic drug, are modulated by the function of ABCG2, which appears to be affected by at least one SNP in its cognate gene ABCG2 in humans. ABCG2 often lowers the bioavailability of other drugs such as rosuvastatin (Keskitalo et al, 2009; Tomlinson et al, 2010), which is widely used to treat dyslipidemia, and sunitinib (Mizuno et al, 2010), a multi-targeted receptor tyrosine kinase inhibitor used in cancer chemotherapy.…”

SurvivalGWAS_Power: a user friendly tool for power calculations in pharmacogenetic studies with “time to event” outcomes

“…The varied collection of design scenarios includes adding a recruitment period, SNP-treatment interactions, and/or different censoring options (for example, withdrawal due to an adverse treatment event). We created these pharmacogenomic study designs after a thorough examination of published studies in the literature [5], including Charland et al [6], Depta et al [7], Wiese et al [8], and Absenger et al [9]. The power calculation is performed by simulating multiple datasets based on the user specified parameter settings and study design options, specifically testing for SNP associations (and SNP-treatment interactions, if required) with the time to event outcome across all simulated datasets.…”