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Elevated ethyl methanesulfonate (EMS) in nelfinavir mesylate (Viracept®, Roche): animal studies confirm toxicity threshold and absence of risk to patients
L. Mueller1, E. Gocke1, P. Larson2, T. Lave1, T. Pfister1
1Roche, Toxicology, Basel, Switzerland, 2Roche, Virology, Nutley, United States
Background: 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 to a global recall of the drug. EMS levels in a daily dose (2500mg Viracept/day) were predicted not to exceed a dose of ~2.75mg/day (~0.055mg/kg/day based on 50kg patient). As existing toxicology data on EMS did not permit an adequate patient risk assessment, a comprehensive animal toxicology evaluation of EMS was conducted.
Methods: General toxicity of EMS was investigated in rats over 28 days. Two studies for DNA damage were performed in mice; chromosomal damage was assessed using a micronucleus assay and gene mutations were detected using the MutaMouse transgenic model. In addition, experiments designed to extrapolate animal exposure to humans were undertaken.
Results: General toxicity study showed that the toxicity of EMS occurred only at doses ³60mg/kg/day, which is far above that received by patients. Studies for chromosomal damage and mutations in mice demonstrated a clear threshold effect with EMS at 25mg/kg/day, under chronic dosing conditions. Exposure analysis (Cmax) demonstrated that ~370-fold higher levels of EMS, than that ingested by patients, are needed to saturate known, highly-conserved, error-free, mammalian DNA repair mechanisms for alkylation.
[EMS Cmax]
Conclusions: Animal studies confirmed that patients who took nelfinavir mesylate with elevated levels of EMS are at no increased risk for carcinogenicity or teratogenicity over their background risk, since mutations are prerequisites for such downstream events. These findings are applicable to >40 marketed drugs that contain mesylate.
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