科研之友
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摘要
Nelfinavir mesylate (Viraceptˋ) is a protease inhibitor for the treatment of HIV-infected patients produced by Roche outside the US, Canada and Japan (in these regions it is manufactured by Pfizer and marketed by Pfizer or Japan Tobacco). It was first introduced by Roche in 1998 following FDA approval in 1997. Although newer protease inhibitors have become available for the treatment of HIV, nelfinavir is seen as a useful medicine for: HIV-infected patients who are intolerant to ritonavir, since it does not require ritonavir PK enhancement (boosting), HIV-infected pregnant women, and HIV patients in resource-limited settings since the formulation is heat-stable and does not require refrigeration.In mid-May 2007, Roche received reports from France and Spain of a strange odour associated with bottles of nelfinavir, including one patient reporting nausea and vomiting. Investigations revealed that there were elevated levels of ethyl methanesulfonate (EMS) in nelfinavir batches produced between March 2007 and May 2007. Further investigation revealed this to be due to manufacturing issues, more specifically failure to dry the hold tank following ethanol cleaning. As EMS is a known alkylating agent that acts on DNA to produce mutagenic and carcinogenic effects in animals, this led to a global recall of the drug on June 6, 2007 facilitated via an extensive communication programme managed by Roche. Subsequent retrospective testing of all nelfinavir batches produced since 1998 showed negligible levels (<1 ppm) in most batches but a few incidences in May 2004 and June 2005 of the presence of approximately 100 ppm of EMS prior to March 2007 [1].Based on the highest amount of EMS found in nelfinavir tables (920 ppm), the EMS levels in a daily dose of nelfinavir (2,500 mg nelfinavir/day [10 tablets]) were shown to result in a daily dose of EMS no higher than ~2.75 mg/day (~0.055 mg/kg/day based on the conservative assumption of a 50 kg patient). As it was crucial to understand th
