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

Pharmacogenomic Variants Affecting Concentrations

Grabar et al.[37] found that carrying the loss-of function CYP2C19*2 allele (rs4244285) was associated with a 71% increase in teriflunomide oral clearance (i.e., clearance/bioavailability) in individuals taking leflunomide. Since CYP2C19 is involved in conversion of leflunomide to teriflunomide, this is likely the result of reduced bioavailability.[37] In the same study, those who carried the gain of function allele (CYP2C19*17, rs12248560) did not demonstrate substantially different concentrations to those who carried the wild-type genotype,[37] most likely because the conversion of leflunomide to teriflunomide was already high in individuals who carried the wild-type (i.e., *1/*1) genotype.

Additionally, a SNP in the ABCG2 transporter (rs2231142, 421C>A) is associated with reduced expression of the transporter protein, and individuals who carry the A allele (i.e., CA or AA genotype) had 41% reduced clearance and a 30% higher maximum teriflunomide concentration after a single dose compared with those who carried the wild-type CC genotype.[60] This implies that decreased secretion of teriflunomide into the gastrointestinal tract is responsible for the reduced clearance in these individuals.

It is possible that teriflunomide concentrations vary significantly between ethnic populations, as carriage of the CYP2C19*2 allele is more common in Asian compared with Caucasian populations (27 vs 16%), and carriage of the ABCG2 421C>A loss of function allele is also more common in Asian compared with Caucasian populations (~30% vs 11%).[57]