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.

Abstract and Introduction

Abstract

Leflunomide is largely considered to be a second-line treatment option for rheumatoid arthritis (RA). Those who fail to respond, tend to progress to treatment with expensive biological agents, which can also be associated with serious toxicities. Optimizing leflunomide treatment to meet the needs of individuals would hence be beneficial in terms of patient outcomes and health care expenditure. In this respect, therapeutic drug monitoring (TDM) may be useful, as plasma concentrations of leflunomide's active metabolite, teriflunomide, correlate with response to treatment, but are highly variable between patients. A number of pharmacogenetic markers have also been identified that influence response and toxicity. Incorporation of these findings into clinical practice could facilitate more efficient use of leflunomide.

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Table 1. Pharmacogenetic effects on leflunomide pharmacokinetics, response and toxicity.
Designation	Effect	Ref.
CYP2C192* allele	Decreased teriflunomide concentrations	[37]
ABCG2 rs2231142 A allele	Increased teriflunomide concentration	[57]
DHODH rs3213422 C allele	Increased response; decreased toxicity	[54,58
DHODH haplotype 2	Decreased response	[56]
CYP1A2 rs762551 CC genotype	Increased toxicity	[53]
CYP2C19 poor and intermediate metaboliser phenotype	Increased toxicity	[55]
ESR1 rs2234693 TT genotype	Increased response	[59]
ESR1 rs9340799 AA genotype	Increased response	[59]