SCIO-469 is a p38α MAP kinase inhibitor being developed to treat rheumatoid arthritis. A Phase I study investigated the safety, PD and PK of single ascending oral solution doses of 0.03 to 5 mg/kg SCIO-469 in young male subjects in the fasted state, and 3 mg/kg SCIO-469 in young male, female and elderly male subjects in the fed state. The PK of SCIO-469 and its two major metabolites were investigated. SCIO-469 was safe and well tolerated. Administration of SCIO-469 resulted in a dose-dependent inhibition of LPS-stimulated TNFα production in a whole blood assay, with the inhibition being similar for the 3- and 5-mg/kg doses (approximately 80% maximum inhibition). SCIO-469 was rapidly absorbed and demonstrated biphasic disposition. The two major metabolites appeared rapidly in plasma with levels at ~25% and 7% of the parent drug, respectively. The elimination half-lives for SCIO-469 and the two metabolites were 6, 11 and 20 hours, respectively. Systemic exposure to SCIO-469 and the two metabolites increased in a broadly dose-proportional manner. Absorption of SCIO-469 was slowed and Cmax was decreased in the presence of food; however, overall systemic exposure was unaffected. Maximum plasma concentrations and systemic exposure to SCIO-469 were lower for female and elderly male subjects compared to young male subjects at a dose level of 3 mg/kg. Clinical Pharmacology & Therapeutics (2004) 75, P54–P54; doi: 10.1016/j.clpt.2003.11.203
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Dereck D. Amakye (2004) studied this question.