Rifalazil(Kaneka corp).
Rifalazil is a rifamycin derivative from Kaneka that is in phase II clinical trials for the treatment of Mycobacterium tuberculosis (M tuberculosis; TB) and AIDS-associated Mycobacterium avium complex (MAC) infections [108254, 165543]. PathoGenesis has licensed the compound exclusively from Kaneka for its development and marketing in the US and Mexico, and is conducting phase I clinical trials in the US for both indications [223964]. In October 1997, Pathogenesis initiated a phase II trial in Brazil in which 60 pulmonary TB patients were enrolled. Fourteen-day dosing regimens in four groups will compare combinations of rifalazil and isoniazid with isoniazid alone or isoniazid plus rifampin. The early bactericidal activity of rifalazil will be evaluated, and results are expected at the end of 1998 [266596,292118]. In phase I clinical trials, low but potentially therapeu-tically useful doses (100 mg) have shown none of the side-effects seen with rifampin therapy. Rifalazil also has a longer half-life than rifampin (24 h compared to 2 to 3 h for rifampin). These trials were completed in 1996 [223964]. In preclinical in vitro studies, rifalazil was 30-fold more potent than rifampin against M tuberculosis and MAC, and has shown efficacy in animal models of tuberculosis and in disseminated MAC infections that have been predictive of clinical efficacy with other antibiotics [224163].The major metabolites, KRM-1671 and KRM-1690 are as active and slightly less active than the parent compound, respectively [187790]. In March 1998, PathoGenesis received a Small Business Innovation Research Grant from the National Institute of Allergy and Infectious Diseases to support antituberculosis research. The company has developed new techniques in automated combinatorial chemistry and microbiological drug susceptibility testing that will expedite its research [282227].
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