Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis

Abstract

IntroductionRational selection of disease modifying anti-rheumatic drugs in the treatment of rheumatoid arthritis (RA) has many potential advantages, including rapid disease control, reduced long-term disability and reduced overall cost to the healthcare system. Inter-individual genetic differences are particularly attractive as markers to predict efficacy and toxicity, as they can be determined rapidly prior to drug selection. The aims of this study, therefore, were to investigate the association between differences in genes associated with the metabolism, clearance and efficacy of leflunomide with its cessation in a group of rheumatoid arthritis patients who were treated with an intensive contemporary, treat-to-target approach.MethodsThis retrospective cohort study identified all individuals who received leflunomide and were enrolled in the Early Arthritis inception cohort at the Royal Adelaide Hospital between 2001 and July 2011. Inclusion criteria were age (>18) and a diagnosis of rheumatoid arthritis. Patients were excluded if a DNA sample was not available, if they withdrew from the cohort or if clinical data were insufficient. Subjects were followed for 12 months or until either another disease modifying antirheumatic drug was added or leflunomide was ceased. The following single nucleotide polymorphisms (SNPs) were determined: CYP2C19*2 (rs4244285), CYP2C19*17 (rs12248560), ABCG2 421C>A (rs2231142), CYP1A2*1F (rs762551) and DHODH 19C>A (rs3213422). The effects of variables on cessation were assessed with Cox Proportional Hazard models.ResultsThirty-three of 78 (42.3%) patients ceased leflunomide due to side effects. A linear trend between cytochrome P450 2C19 (CYP2C19) phenotype and leflunomide cessation was observed, with poor and intermediate metabolizers ceasing more frequently (adjusted Hazard Ratio = 0.432 for each incremental change in phenotype, 95% CI 0.237 to 0.790, P = 0.006). Previously observed associations between cytochrome P450 1A2 (CYP1A2) and dihydro-orotate dehydrogenase (DHODH) genotype and toxicity were not apparent, but there was a trend for ATP-binding cassette sub-family G member 2 (ABCG2) genotype to be associated with cessation due to diarrhea.ConclusionsCYP2C19 phenotype was associated with cessation due to toxicity, and since CYP2C19 intermediate and poor metabolizers have lower teriflunomide concentrations, it is likely that they have a particularly poor risk:benefit ratio when using this drug.

Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity

“…In fact, the mitochondrial membrane potential of primary rat hepatocytes did show more sensitive to LEF than Figure S1). Many reports demonstrated that the polymorphism of several CYPs, such as CYP1A2 and CYP2C19, could affect the liver toxicity of LEF in patients with rheumatoid arthritis [24][25][26] , which could be indirect evidences that CYPs play a critical role in the detoxification of LEF in the body. Our studies with HRN mice are the first direct in vivo evidences that hepatic CYPs are involved in the clearance and toxicity of LEF.…”

Pharmacokinetic evaluation of teriflunomide for the treatment of multiple sclerosis

“…However, the incidence of hepatotoxicity with teriflunomide may be lower than with the parent leflunomide. Leflunomide is metabolized to teriflunomide by CYP enzymes, including CYP2C19, and it has been shown that toxicity of leflunomide appears to be related to CYP2C19 phenotype, with poor metabolizers having an increased rate of toxicity [81]. In addition, in vitro studies have shown that leflunomide-mediated hepatotoxicity can be inhibited by administration of a pan CYP enzyme inhibitor and that hepatotoxicity is related to hepatic activation of leflunomide, possibly via the formation of a toxic metabolite.…”

“…The one caveat is that other drugs used concurrently with leflunomide for RA, notable methotrexate, may have a synergistic effect at causing these adverse reactions, in particular nausea, neutropenia, alopecia and pneumonitis. However, there is some preliminary evidence to suggest that hepatotoxicity may be less common with teriflunomide compared with leflunomide [80,81], while opportunistic infections and effects in pregnancy are worthy of special consideration.…”

Drug metabolism and hypersensitivity reactions to drugs

“…Leflunomide is metabolized by polymorphic phase I enzymes, particularly CYP1A2 (cytochrome P450 1A2), CYP2C and CYP3A4 (cytochrome P450 3A4), but studies [66][67][68][69][70][71] addressing the role of altered metabolism genetically determined and the risk of developing hypersensitivity reactions to leflunomide are still insufficient.…”