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Teratogen Update: Reproductive Risks of Leflunomide (Arava™); a Pyrimidine Synthesis - page 9 / 21





9 / 21

Compared to the Cmax levels in rats and rabbits which did not cause embryotoxicity or teratogenicity, the level of 0.03 g/ml is 123 times (compared to rat) and 136 times (compared to rabbit) lower than the blood level in the rat and rabbit which has been determined as the no-effect level.

Compared to AUC in rats and rabbits, the level of 0.72 gh/ml is 25 times (compared to rat) and 72 times (compared to rabbit) lower than the blood level in the rat and rabbit which has been determined as the no-effect AUC level

Scientifically these safety margins are sufficient. It is highly probable that the safety margins are even higher. It has been shown that the pharmacodynamic effects of leflunomide, namely dihydroorotate dehydrogenase (DHO-DH) inhibition and anti-proliferative activity, considered to be responsible for the embryotoxic and teratogenic effects, are species-specific  and significantly different. The inhibitory effect of leflunomide on DHO-DH activity is 40 times, and its antiproliferative effect on cell cultures is 300 times stronger in rat than in man. However, since it cannot be determined whether the human embryo or fetus is more sensitive than the adult, these species differences and possible consequences on safety margins cannot be considered for estimating the reproductive risks of leflunomide in humans.

The average steady state plasma level of the active metabolite of leflunomide in Phase III studies was between 30 and 40 g/ml. This is derived from the average clearance of 24 ml/h, which is given in the Population Kinetics report (Css=(dose/time)/CL = (20/24)/24 = 35 mg/L). The safe human level is 0.03 mg/L, i.e. a factor of 1,000 or approximately 10 half-lives. Thus, if a woman treated with leflunomide wants to become pregnant, the medication has to be stopped and cholestyramine or charcoal has to be administered repeatedly to decrease the blood levels rapidly to a level which is considered not to cause an increased teratogenic or reproductive

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