OVERVIEW OF TOXICOLOGICAL DATA ON RIFABUTIN

Rifabutin is a wide spectrum antibiotic particularly active on atypica l and rifampicin-resistant mycobacteria. Rifabutin is more potent than rifampicin on Mycobacterium tuberculosis in vitro. Its mode of action is characterized by a high intracellular penetration in treated indiv iduals. Clinical trials have proven the therapeutic value of rifabutin especially in AIDS patients with concomitant MAC. The preclinical saf ety evaluation of this compound included single and repeated dose toxi city studies of up to one year in rodents and non-rodents, reproductio n and carcinogenicity city studies and mutagenicity tests. During toxi cological studies the most significant finding after repeated administ ration of rifabutin was the presence of multinucleated hepatocytes (MN H) in rats. This is a species specific finding which did not affect th e life span of the hepatocytes. As shown in carcinogenicity studies, t here was no tendency to further proliferative changes. Another specifi c histological feature among the species studied was the presence of a lipofuscin-like brown pigment, which was seen in many organs. This is a common finding with amphipilic compounds, such as rifabutin, which bind lipids and proteins, forming membrane-bound complexes. Even in ca rcinogenicity studies this change did not constitute a stimulus to cel l proliferation and did not cause any secondary changes. In rodents, t here was a mild hemolytic anemia at doses higher than 10 mg/kg/day. At doses ranging from 160-200 mg/kg/day rifabutin inhibited the function s of the male gonads in rats. This effect was reflected in a reduction of implantations observed in the fertility studies. Doses of 40 mg/kg /day did not induce any embryotoxic effects or changes in reproductive performance. The drug was not genotoxic and was devoid of carcinogeni c potential. The exposure levels in the animals used for toxicological tests were higher than those reached in man at therapeutic doses.