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


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

In This Article

Concentration–Response Relationship

Previous studies have identified a relationship between teriflunomide concentration and effect in patients with RA, but the reported response thresholds have been highly variable. Van Roon et al.[45] indicated improved response in those with concentrations over 16mg/l while Chan, Charles and Tett[48] recommended concentrations >50mg/l to optimize response.[37,45,48] These discrepancies have been difficult to resolve, but may be explained by small sample sizes and the natural heterogeneity of the patient population, particularly in regards to disease duration, severity, other therapies and a lack of information regarding genetic polymorphisms. Furthermore, the disease outcome measures used between the studies varied. Van Roon et al.[45] used a composite measure of disease activity (the 28-joint disease activity score [DAS28]), whereas Chan, Charles and Tett[48] used a swollen joint count combined with a 36 item short form physical and mental health summary (a general quality of life survey which provides different information about the effects of a patient's RA). Despite this, the concentration-effect relationship has been consistently observed, and considering the linear pharmacokinetics and reproducible concentrations within an individual over time, support a role for TDM to inform individualised leflunomide dosing.[33,47] Given the variability of teriflunomide pharmacokinetics between individuals, Van Roon et al.[45] reported that up to 50% of their study participants had levels below their identified threshold concentration (16 mg/l), which supports the potential for the cautious introduction of leflunomide at doses above the currently recommended maximum of 20 mg per day in patients who have low plasma concentrations, no side effects and inadequate response. Additionally, Phase III studies of oral teriflunomide have also shown a concentration-dependent improvement in response in MS suffers, where higher concentrations are associated with decreased relapse rates and fewer active lesions.[34]

To date, no relationship between teriflunomide concentrations and adverse drug events in RA patients has been identified. However, studies examining this relationship have utilised a retrospective recruitment strategy and have hence only examined patients who have been taking leflunomide for relatively long periods of time.[37,45,48] There has therefore been a selection bias towards patients tolerant of leflunomide, as many of the side effects (primarily gastrointestinal) decrease over time, and patients with other serious side effects would have ceased treatment before study initiation.

Interestingly, TDM of teriflunomide is recommended when used off licence in kidney transplant recipients with BK-virus nephropathy, although the recommended teriflunomide concentration of> 40 mg/l is based upon achieving viral clearance rather than immunosuppressive effects.[9–11,49] However, the concentration threshold is quite similar to that of the previous studies in RA,[37,45,48] but the mean oral dose required to achieve this concentration in a population of transplant patients was approximately 40 mg daily,[49] twice that of the maximum recommended dose of 20 mg daily in patients with RA.

For many drugs, free concentration is more predictive of response and toxicity than total concentration, particularly for those with a high degree of protein binding, such as teriflunomide, where the total concentration may be a poor surrogate of the free concentration.[50] Figure 3 represents matched total and free teriflunomide concentrations in 55 RA patients treated with leflunomide (unpublished data); as determined, via LC–MS/MS with Rapid Equilibration Dialysis (RED) plates according to manufacturer's instructions (ThermoFisher, USA).[47] The samples were available from an updated cohort as represented in our Rakhila et al.[47] study. Although there was a strong relationship between total teriflunomide and free teriflunomide concentrations (p< 0.001), substantial variability remained. Measurement of free teriflunomide concentrations warrant further investigation as a predictor of response (and toxicity), and once again research in the field of leflunomide's off-label use in the treatment of transplant recipients with BK-virus is leading the way. Hüttemann et al.[10] compared free and total teriflunomide concentrations to therapeutic outcomes in 20 kidney transplant recipients with BK-virus receiving leflunomide. Hüttemann et al.[10] found that free teriflunomide concentrations were strongly associated with leukopenia (p< 0.05) although there was no association with markers of efficacy (i.e., viral load, serum creatinine and kidney histology).

Figure 3.

Comparison of total teriflunomide concentrations against free concentrations.

Factors Affecting Teriflunomide Concentration & Effect

Since total teriflunomide concentrations are highly variable, numerous studies have been conducted to determine the cause of this variability and subsequently to inform dosage recommendations. Increasing age and decreased body weight have been associated with higher steady state teriflunomide concentrations, while liver function, renal function and smoking status can also influence teriflunomide concentrations.[37,48,51] However, the correlation with these variables is low and not particularly useful in predicting teriflunomide concentrations in an individual.

Attention has thus turned to pharmacogenomic variables. The rationale for pharmacogenomic testing is that consideration of genetic differences which contribute to inter-individual variation in teriflunomide concentrations could facilitate personalized dosing decisions. Genetic markers can be easily and rapidly determined from a small blood sample, and thus are an attractive biomarker for this purpose. Nonetheless, despite numerous studies indicating that various single nucleotide polymorphisms (SNPs) influence teriflunomide pharmacokinetics and pharmacodynamics, they have not yet been used to develop dosing recommendations. This may be due to the fact that studies are yet to perform multivariate analyses, particularly in conjunction with TDM. While large studies investigating environmental factors in conjunction with RA susceptibility genes are limited, they may prove important. For example, the recently described interaction between body mass index and increased methotrexate toxicity in those the carrying the minor alleles of rs12651804 (in Cardiomyopathy Associated 5 [CMYA5]) and rs1504582 (a SNP located near chemokine (C-C mMotif) ligand 2 [CCL2], a pro-inflammatory mediator that is commonly unregulated in RA).[52] Additionally future studies should assess genetic variants in the context of ethnicity, as studies have thus far been largely conducted with small Caucasian groups.[53–56] Nonetheless it is important to have a firm understanding of the potential pharmacogenomic variants (Table 1), as they may be the key to pre-emptively determining suitable doses for patients, and identify those who are likely to fail therapy, as well as guiding future research.