Time-to-event model of leflunomide cessation due to toxicity in rheumatoid arthritis patients: Genetic polymorphism of CYP1A2 but not total or free teriflunomide concentrations is associated with cessation.

Leflunomide is used in the treatment of rheumatoid arthritis (RA), yet approximately 20 to 40% of patients cease due to toxicity. The aim was to develop a time-to-event model describing leflunomide cessation due to toxicity within a clinical cohort, and to investigate potential predictors of cessation such as total and free teriflunomide exposure and pharmacogenetic influences.
This study analysed individuals who received leflunomide and were enrolled in the Early Arthritis inception cohort at the Royal Adelaide Hospital between 2000 and 2013. A time-to-event model in NONMEM was used to describe the time until leflunomide cessation. Teriflunomide exposure, including predicted steady-state total and free teriflunomide concentrations (determined from a previously presented semi-physiological model) were analysed for a potential influence on cessation as well as numerous pharmacogenetic variants. The random censoring of individuals was also simultaneously described. The clinical relevance of significant covariates were visualised via simulation.
Data from 105 patients were analysed, with 34 ceasing due to toxicity. The baseline dropout hazard and baseline random censoring hazard were best described by step functions changing over discrete time intervals. No statistically significant influences of teriflunomide exposure metrics were identified. Of the screened covariates, carriers of the C allele of CYP1A2 rs762551 had a 2.29 fold increase in cessation hazard compared to non-carriers (95%CI= 2.24 – 2.34, p=0.016).
A time-to-event model described the time between leflunomide initiation and cessation due to side effects. The C allele of CYP1A2 rs762551 was linked to increased leflunomide toxicity, while no association with teriflunomide exposure was identified, highlighting that future studies should focus upon the investigation of potential toxic metabolites.