Enhanced Phase I FAQs

The MIST Guidance is a document produced by the FDA entitled ‘Safety Testing of Drug Metabolites’ in February 2008 to clarify their position on when metabolites should be identified and characterized. It applies to small molecule drug candidates only.

The guidance document states that the FDA “strongly recommend in vivo metabolic evaluation in humans be performed as early as possible”. Metabolites that raise a safety concern are those produced in humans at greater than 10% of parent drug systemic exposure at steady state.

A cost effective first view on human metabolism using samples derived from a microtracer enhanced Phase I clinical study

Human plasma profiles of new drug candidates are not accurately predicted by in vitro systems and preclinical species are not always representative. Reliable quantitative data for important circulating metabolites result only from a human radiolabel study. Radiolabel studies in humans and data on circulating metabolites are best obtained as soon as possible in clinical development before long-term preclinical studies commence. Traditional human radiolabel studies are expensive. When an early ADME study is performed, our clients can obtain a human metabolite profile early and very cost-effectively. Any decision before the human radiolabel study is made at risk and may need to be re-evaluated after radiolabel data is available.

The technique of choice is ultra-sensitive Accelerator Mass Spectrometry (AMS). Conventional analytical methods, such as LSC, are insufficiently sensitive.

A single uncomplicated first view of human metabolism which can be compared with chromatograms obtained from preclinical in vitro and in vivo studies.

Xceleron has developed a number of options to address this issue. Study designs are likely to be compound dependent. Please contact us for further information.