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

Pharmacokinetics–Pharmacodynamics of Leflunomide


Both leflunomide and its active metabolite teriflunomide, have a molecular mass of 270.2 g, with the structure of the latter differing only by the ring opening indicated in Figure 1.[33] Leflunomide is almost completely metabolised during its first pass and is undetectable within plasma. The approximate bioavailability to the active metabolite teriflunomide is approximately 70%.[34,35] This, and the fact that teriflunomide appears to be completely bioavailable are the basis of oral teriflunomide dosing guidelines: the recommended daily dose of 7 or 14 mg daily in patients with MS is equivalent to 10 and 20 mg daily of leflunomide in RA patients.[34] The conversion of leflunomide to teriflunomide is largely mediated by the cytochrome p450 (CYP) enzymes 1A2, 2C19 and 3A4, but it is also reported to rapidly degrade to teriflunomide in the blood.[33,36–37]

The volume of distribution of teriflunomide is approximately 11 l, consistent with a high degree of plasma protein binding (>99%) which has been shown to be linear to a concentration of 537 mg/l.[34,38] Following IV teriflunomide administration, clearance is approximately 30.5 ml/h, probably because of significant enterohepatic recycling (likely mediated in part by the ABCG2 transporter protein), and the half-life is approximately 2 weeks (mean ~15.7 days).[33,39] As a result, initial guidelines for commencing leflunomide treatment recommended a loading dose of 100 mg daily for 3 days, aiming to achieve a steady state concentration more rapidly. However, this approach was associated with increased discontinuation due to side effects, particularly nausea and diarrhoea, with no incremental increase in efficacy.[7,28,40] Hence, leflunomide is now commonly initiated at a daily dose of 10 mg, which is up-titrated to 20 mg if disease remains active and there are no significant side effects. Furthermore, recent studies have shown that no dose modification is required for end stage renal patients receiving haemodialysis or peritoneal dialysis.[41,42]

Following leflunomide discontinuation teriflunomide may still be present within the plasma after 2 years.[30] A washout procedure with cholestyramine (a bile acid binding resin) is able to rapidly decrease teriflunomide plasma levels via inhibition of enterohepatic recycling, effectively reducing the elimination half-life to 1–2 days.[34] The recommended wash-out procedure is the use of cholestyramine 8 g three times daily for a cumulative period of eleven days. Successful washout (plasma levels are < 0.02 mg/L) is confirmed by the measuring teriflunomide concentrations on two separate occasion 14 days apart.[30] The washout procedure should be performed where serious toxicity occurs such as hepatotoxicity, pancytopenia, interstitial lung disease or in patients who have experienced an allergic reaction. Additionally, as leflunomide is teratogenic, the washout should be conducted when pregnancy occurs or is planned, with a recent study indicating no increased risk of toxicity in those who initiated the washout early in pregnancy compared with individuals who were never exposed to leflunomide.[30,43]

Within the body, the primary route of elimination is via biliary excretion of teriflunomide.[35] Teriflunomide also undergoes slow degradation via hydrolysis, hydroxylation and oxidation with secondary oxidation, n-acetylation and sulphate conjugation.[34,44] In vitro studies with human hepatocytes indicate that teriflunomideis stable for 4 h, while another small study with human microsomes found little degradation after 2 h, with 1.2 and 4.4% converted to 4-TFMA oxanilic acid and 4-TFMA glycolanilide respectively.[34–35,44] The pharmacokinetic properties of leflunomide and teriflunomide are represented in Figure 2.

Figure 2.

Metabolism, protein binding, enterohepatic recycling and elimination of leflunomide and teriflunomide.

Teriflunomide Concentrations

Peak plasma teriflunomide concentrations occur approximately 2.3 h after both oral leflunomide and oral teriflunomide dosing.[34] In individuals taking oral leflunomide, total teriflunomide steady state plasma concentrations have been shown to be highly variable between patients,[37,45–46] ranging from 15 – 98 μg/ml and 3 – 150μg/ml in individuals taking 10 and 20 mg doses, respectively. Intra-individual variability appears small and individualised dosing appears feasible, with 75% of a cohort of patients displaying steady state trough samples within ±15% of the concentration 6 weeks earlier, indicating that concentrations appear reproducible over time.[47]

Similarly, following oral teriflunomide administration, steady state plasma concentrations are variable. In a study of patients with MS taking 7 and 14mg daily doses of teriflunomide, concentrations ranged between 0.1 to 235 μg/ml, and MS was not seen to appreciably affect teriflunomide pharmacokinetics compared with healthy subjects.[34,44] The high variability of plasma teriflunomide concentrations following oral leflunomide and teriflunomide dosing appears to indicate the importance and high variability of enterohepatic recycling between individuals, via either intestinal secretion or reabsorption pathways.[44] It is unclear whether variability in conversion of leflunomide to teriflunomide also contributes significantly to the inter-patient variability in patients with RA.