Willi Weber, Lutz Harnisch, Christian Rokitta, Jonathan Collins, H.-Juergen Roethig
Clinical Research, Hoechst Marion Roussel, Frankfurt, Germany
Leflunomide is an isoxazole immunosuppresive agent with clinically proven efficacy in rheumatoid arthritis. Following oral administration, the highly non-polar prodrug leflunomide is rapidly and completely absorbed. During first-pass it is completely metabolised mainly into its active (primary) metabolite M1. The binding of M1 to plasma-proteins, predominantly albumin, is > 99 %. M1 is a non-polar metabolite which is very slowly transformed into the polar secondary metabolites, which in turn are rapidly excreted mainly in urine. Unchanged M1 however is excreted from the body very slowly only in faeces. The elimination half-life (t1/2) of M1 is approximately 2 weeks.
In vitro studies have shown that both activated charcoal powder (CC) as well as cholestyramine (CT) have a high binding capacity for M1. Thus, it was investigated whether either CC or CT given orally could increase extraction of M1 from the body. 48 healthy volunteers received doses of 20-100 mg leflunomide followed by either CC or CT administration 1 to 5 days later. Pharmacokinetic profiles of M1 were modelled using NONMEM. The binding of M1 to CC / CT was considered an additional clearance process. The results revealed that CC / CT induced clearance of M1 is approximately 10 times higher than the physiological clearance. The administered doses of CC / CT removed about 50 % of systemically available M1 within 2-12 hours.
The CC / CT effect can be explained by assuming an entero/enteric and/or entero/hepatic recirculation of M1. By administration of such binding materials into the gut lumen the recirculation of M1 is interrupted. Instead M1 binds to the CC / CT and is then excreted unchanged in faeces. Therefore in the event of toxicity or overdose CC / CT can be administered to reduce exposure of drug to the patient.
Reference: PAGE 5 (1996) Abstr 568 [www.page-meeting.org/?abstract=568]
Poster: oral presentation