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Systemic Availability of the Active Metabolite Hydroxy-Fasudil After Administration of Fasudil to Different Sites of the Human Gastrointestinal Tract

From the US Food and Drug Administration (FDA), Center for Drug Evaluation, Office of Clinical Pharmacology and Biopharmaceutics, Rockville, Maryland (Dr Hinderling); Berlex Pharmaceuticals, Montville, New Jersey (Dr Karara, Dr Lu); Sankyo Pharma Development, Edison, New Jersey (Mr Tao); Huntingdon Life Sciences, United Kingdom (Dr Pawula); and Pharmaceutical Profiles Ltd, United Kingdom (Dr Wilding).

This study evaluated the gastrointestinal absorption of fasudil, a novel Rho kinase inhibitor for the treatment of stable angina, at different sites using remote-controlled capsules and assessed the feasibility of developing an extended-release formulation. Ten healthy male volunteers were enrolled, and 8 subjects completed this single-dose, open-label, randomized, 5-way crossover study. Forty milligrams of fasudil HCl was administered as solution to the distal ileum and ascending colon, as powder to the ascending colon, and orally as an immediate-release tablet and solution. All treatments were well-tolerated and no serious adverse events were observed. The mean systemic availabilities of M3 relative to the oral solution were 1.04 (distal ileum, solution), 1.14 (ascending colon, solution), 1.27 (ascending colon, powder) and 1.04 (oral tablet), indicating similar systemic availability of M3 after administration of fasudil HCl to different gastrointestinal sites. The results suggest that development of a once-a-day extended-release formulation for fasudil HCl should be readily achievable.

Key Words: Fasudil • hydroxyl-fasudil • antianginal drug • gastrointestinal tract • Rho kinase • site of drug absorption • remote-controlled capsule

Address for reprints: Ming Lu, PhD, Clinical Pharmacology Department, Berlex Pharmaceuticals, PO Box 1000, Montville, NJ 07045.

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