Elevated ethyl methanesulfonate (EMS) in nelfinavir mesylate (Viracept, Roche): overview.
作者： Anton Pozniak , Lutz Muller , Miklos Salgo , Judith K Jones , Peter Larson
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摘要: Roche's protease inhibitor nelfinavir mesylate (Viracept®) produced between March 2007-June 2007 was found to contain elevated levels of ethyl methanesulfonate (EMS), a known mutagen (alkylator) – leading global recall the drug. EMS in daily dose (2,500 mg Viracept/day) were predicted not exceed ~2.75 mg/day (~0.055 mg/kg/day based on 50 kg patient). As existing toxicology data did permit an adequate patient risk assessment, comprehensive animal evaluation conducted. General toxicity investigated rats over 28 days. Two studies for DNA damage performed mice; chromosomal assessed using micronucleus assay and gene mutations detected MutaMouse transgenic model. In addition, experiments designed extrapolate exposure humans undertaken. A general study showed that occurred only at doses ≥ 60 mg/kg/day, which is far above received by patients. Studies mice demonstrated clear threshold effect with 25 under chronic dosing conditions. Exposure analysis (Cmax) ~370-fold higher than ingested patients, are needed saturate known, highly conserved, error-free, mammalian repair mechanisms alkylation. summary, suggested patients who took no increased carcinogenicity or teratogenicity their background risk, since prerequisites such downstream events. These findings potentially relevant >40 marketed drugs salts.
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