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Teratogen Update: Reproductive Risks of Leflunomide (Arava™); a Pyrimidine Synthesis - page 8 / 21





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slightly increased in plasma from patients with RA and was approximately doubled in patients with chronic renal insufficiency, but in both healthy subjects, patients with RA and patients with renal insufficiency, the unbound active metabolite represented less than 2% of the total seurm concentration.  The extensive protein binding of the active metabolite is consistent with its low volume of distribution.

Oral administration of activated charcoal or cholestyramine is effective in enhancing the elimination of the active metabolite. During oral administration of activated charcoal (50 gm four times a day) or cholestyramine (8 gm three times a day), the half-life of the active metabolite decreased to approximately 24 hours. Although the mechanism for the enhanced elimination is unknown, it may be related to interruption of enterohepatic recycling and/or dialysis across the gastrointestinal mucosa.

When subjects with end-stage renal disease were administered a single 100 mg dose of leflunomide orally, plasma concentrations of the active metabolite, both prior to and after dialysis (chronic ambulatory peritoneal dialysis [CAPD]) or hemodialysis), were comparable to those of healthy volunteers administered the same dose.  Due to its high protein binding, the active metabolite is not significantly removed by dialysis.

C.  Preclinical Reproductive Studies:  In oral embryotoxicity and teratogenicity studies in rats and in rabbits, leflunomide was embryotoxic (growth retardation, embryolethality) and teratogenic (in rats, malformations of the head, rump, vertebral column, ribs and limbs; in rabbits, malformations of the head and bilateral dysplasia of the spine of the scapula). The no-effect level for embryotoxicity and teratogenicity in rats and rabbits was 1 mg/kg body weight, which is equivalent to 18.32 and 52.5 g/ml, respectively.

A blood level of 0.03 ug/ml and an AUC of 0.72 gh/ml are regarded as safe based on the following considerations:

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