Individualization of Leflunomide Dosing in Rheumatoid Arthritis Patients

Ashley M Hopkins; Catherine E O'Doherty; David JR Foster; Richard N Upton; Susanna M Proudman; Michael D Wiese

Disclosures

Personalized Medicine. 2014;11(4):449-461. 

In This Article

Future Perspective

Enhanced treatment strategies which effectively meet clinical outcomes for RA patients and are economically viable are essential in current practice. Based upon the evidence, leflunomide and consequently teriflunomide are candidates for personalized dosing for use in RA. The small unbound fraction of teriflunomide within the blood makes measurement of free teriflunomide concentrations an interesting prospect for TDM, but adequately powered studies in patients taking leflunomide are needed to identify the free teriflunomide concentration-effect profile. Such information should be considered in the context of patient demographics as well as the numerous pharmacogenomic markers that have been correlated to response and/or toxicity with leflunomide. Such an approach may lead to identification of genetic based target concentrations. Furthermore, as leflunomide is often used in combination with other DMARDs, teriflunomide concentration-effect and concentration-toxicity relationships should be investigated in the context of concurrent DMARD therapy. Epigenetic changes have also been identified as markers that can explain intra and inter-individual drug response and toxicity, and, although this is not well defined in patients who take leflunomide such changes in genes involved in leflunomide pharmacokinetics and pharmacodynamics may also be identified as important markers.[77] Whilst the effect of epigenetic changes in genes encoding drug metabolising enzymes can be captured by therapeutic drug monitoring, epigenetic alterations are likely to be more important if they occur in genes involved in leflunomide pharmacodynamics (e.g., DHODH), and this has the potential to further improve personalized treatment approaches with leflunomide.

Oral teriflunomide is also an interesting prospect for dosage individualisation, although it is yet to be studied as thoroughly as leflunomide (particularly in RA), teriflunomide concentrations achieved clinically have still been shown to vary widely. While variants in genes that encode proteins involved in leflunomide's pharmacokinetics and pharmacodynamics are still likely to influence oral teriflunomide response. Therefore, oral teriflunomide remains a candidate for TDM and pharmacogenomic guided therapy, but unlike leflunomide, it is not metabolized by CYP enzymes, which have been linked to leflunomide toxicity and thus teriflunomide may have superior tolerability. This may lead to the potential introduction of the loading dose with oral teriflunomide in RA, where steady state concentrations can be achieved more rapidly as guided by TDM, while avoiding high toxic metabolite concentrations which would occur in some patients with a fixed 100 mg of leflunomide daily for 3 days. This may be particularly useful if an adjusted dosing strategy was used, for example 7 mg three times a day for one week followed by TDM guided dosing; rather than a 100 mg leflunomide dose which appears to predispose to gastrointestinal toxicity secondary to extremely high teriflunomide, leflunomide or toxic metabolite concentrations formed by CYP enzymes.

The integration of personalized dosing of leflunomide or teriflunomide into clinical practice requires further research, but as has been shown, multiple factors including concentrations and genetics may affect response to therapy and could influence the currently restrictive dosing guidelines on leflunomide at either 10 or 20 mg daily. Future studies will require large prospective cohorts with multivariate analyses of total and free teriflunomide and consider the results in the context of concurrent DMARDs and genetic variants.

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