teratogenic potential, because there are no data on leflunomide’s effect on the human embryo. Therefore, the conservative approach is to be concerned that therapeutic blood levels of the active metabolite of leflunomide represent a teratogenic risk.
Based on the no-effect level of leflunomide for teratogenicity and other reproductive effects as determined from in vivo animal studies and the fact that reproductive effects from intrauterine exposures are deterministic (threshold) effects, there should be no teratogenic risk at blood levels that are 10 fold lower than the no-effect blood level of leflunomide. A 100 fold reduction in blood level would present no teratogenic risk and would be an extremely conservative level that should provide an environment for embryonic and fetal development that does not have a measurably increased risk. Therefore, if the blood level of the active metabolite is lowered to < 0.02 g/ml, there is no likelihood of a teratogenic risk. This is based on the FDA recommendation that the cholestyramine washout attain non-measurable levels of leflunomide as determined by HPLC and this level is < 0.02 g/ml. This can be readily accomplished with the eleven day cholestyramine washout. It should be pointed out that 100 fold reduction below the no-effect level is an extremely conservative approach. A 10 fold reduction below the no-effect level is also likely to represent no measurable teratogenic risk. This may be important in evaluating inadvertent exposures in unintended pregnancies.
2) Is there a teratogenic risk due to the presence of 4-trifluoromethylaniline (TFMA), a minor metabolic product of leflunomide?
TFMA (4-trifluoromethylaniline) represented less than 5% of the metabolic products of leflunomide and was present in nanogram quantities in human pharmacokinetic studies. Therefore, the concentrations of TFMA attained following therapeutic administration of leflunomide are too low to represent a teratogenic risk.