title: Meeting the MIST regulations: human metabolism in Phase I using AMS and a tiered bioanalytical approach.
abstract: The metabolites in safety testing and ICH-M3 guidance documents emphasize the importance of metabolites when considering safety aspects for new drugs. Both guidances state that relevant metabolites should have safety coverage in humans (although the guidelines have different definitions of relevant metabolites). Not having safety coverage for important metabolites in humans may cause significant delay in the overall pharmaceutical development program. This article discusses the regulatory background regarding safety and metabolites, as well as outlines an integrated strategy taken by one pharmaceutical company, Lundbeck A/S. Lundbeck uses metabolite exposure data from first-in-man studies, obtained using an accelerator MS approach followed by a two-tiered bioanalytical investigation. This enables early availability of key data on this aspect and, overall, represents a powerful risk mitigation strategy.
authors.affiliation: Xceleron Inc., Germantown, MA, USA. graham.lappin@xceleron.com
authors.forename: Graham
authors.initials: G
authors.lastname: Lappin
authors.forename: Mark
authors.initials: M
authors.lastname: Seymour
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gross
authors.forename: Martin
authors.initials: M
authors.lastname: Jørgensen
authors.forename: Morten
authors.initials: M
authors.lastname: Kall
authors.forename: Lisbet
authors.initials: L
authors.lastname: Kværnø
mesh_terms: D019540:Area Under Curve; D001682:Biological Availability; D001711:Biotransformation; D002250:Carbon Radioisotopes / Q000032:analysis*; D002851:Chromatography, High Pressure Liquid; D017321:Clinical Trials, Phase I as Topic; D004353:Drug Evaluation, Preclinical / Q000379:methods* / Q000592:standards; D064420:Drug-Related Side Effects and Adverse Reactions; D015507:Drugs, Investigational / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods*; D017410:Practice Guidelines as Topic
chemical_list: D002250:Carbon Radioisotopes; D015507:Drugs, Investigational