人体药物代谢产物安全评估在早期临床试验中的应用研究.pdf

Approaches to assess human metabolites in early clinical trials through MIST 人体药物代谢产物安全评估在早期临床试验中的应用研究 文波 Bo Wen GlaxoSmithKline R&D, King of Prussia, PA 19406, USA 2018南京国际药代会议, 南京曙光国际大酒店, 2018年6月29 日~7月1 日 th th 2018 Nanjing International DMPK Symposium, June 29 – July 1 , Nanjing, China Outline • Background - Why human metabolism? • Stable drug metabolites (“MIST”) - FDA and ICH guidances • ‘Human first’ metabolism strategy - Can we MIST human first? 2 Human metabolism What it is? – Structure HO O N H Where it is? - Distribution OH OH How much there is? – Quantification 60% dose (faeces) OH HO O How it happened? - Mechanism N H OH Where it goes? – Excretion OH What it did? – Safety vs efficacy vs inert Human metabolism - why Toxic Toxicity metabolite Enhanced Active activity Drug metabolite Altered