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Teratogen Update: Reproductive Risks of Leflunomide (Arava™); a Pyrimidine Synthesis - page 7 / 21





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population pharmacokinetic analysis of RA patients enrolled in pivotal safety and efficacy studies.

After single doses of leflunomide to healthy subjects, peak plasma concentrations of the active metabolite were approached between 6 and 12 hours. Plasma concentrations then declined monoexponentially, with a half-life of approximately 8 days.  Based on determination of the active metabolite, the bioavailability of leflunomide from a tablet formulation relative to an oral solution was 80%. Arava™  administered with a high fat/high carbohydrate meal was bioequivalent to administration under fasting conditions. Arava™  can therefore be taken without regard to meals.

In a 24-week study in patients with RA, steady-state was reached between 7 and 8 weeks. Mean plasma concentrations of the active metabolite, 24 hours after a 100 mg loading dose (8.5 g/ml), were twice those after a 50 mg loading dose (4.0 g/ml).  Pre-dose plasma concentrations after 24 weeks of dosing were linearly related to the maintenance dose (9, 18, and 63 g/ml after 5, 10 or 24 mg/day, respectively) and the elimination half-life averaged 14 - 18 days. The pharmacokinetics of the active metabolite are, therefore, linear over the range of loading and maintenance doses to be used clinically.

Based on the half-life in this patient population and the recommended dosing interval (24 hr), a loading dose is needed to yield steady-state concentrations more rapidly. It is recommended that a 300 mg loading dose be administered as a single 100 mg dose per day for 3 days.

In studies with plasma samples obtained from healthy subjects, the active metabolite was extensively bound to protein (albumin).  The unbound fraction was 0.62%.  Binding of the active metabolite was linear up to 573 g/ml.  Compared to healthy subjects , the unbound fraction was

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