3. Using pre-clinical information to establish a safe dose in first-in-men studies

Team: Dr Lisa Hampson (Lancaster University), Dr Arturo Di Cosmo (ABC Farmaceutici)
Clinical Advisor: Prof Malcolm Macleod
, Professor of Neurology and Translational Neuroscience at the University of Edinburgh and head of Neurology at Forth Valley Royal Hospital. He co-ordinates the collaborative approach to meta-analysis and review of animal data in experimental studies (CAMARADES).
Location: Lancaster University (Lancaster, UK)

Before a novel compound is evaluated in a series of clinical trials, a number of pre-clinical, in-vitro and in-vivo studies are typically undertaken. A crucial step in the transition between pre-clinical and clinical studies is to extrapolate a dose that has been established as safe (and efficacious) in animal studies to a safe dose to be used in first-in-men studies. This is usually done using allometric scaling, a process that adjusts the dose found in a particular animal species to other species and ultimately humans based on the typical weight. This process is, however, often poorly understood and often applied incorrectly.3

The project will begin by investigating current practice when determining the starting dose for first-in-men studies and a review of existing methods for dose extrapolation. A model which dynamically updates the extrapolated best dose based on accumulating data in the first-in-men study such that the weight of the preclinical evidence is gradually reduced for direct information in humans is then developed. A Bayesian framework that synthesizes the pre-clinical evidence which is subsequently updated with observations in the study in humans will be utilized.

Meet our Early Stage Researcher: Haiyan Zheng, Lancaster University

Haiyan Zheng_new

I joined Lancaster University in 2015. Prior to moving to the UK, I graduated with a MSc in Biostatistics from Osaka University (Japan), where I found research topics including clinical trial designs, multiple testing procedures and survival analysis have been particularly fascinating. My master thesis was about the optimal use of surrogate endpoint at the interim in two-stage adaptive enrichment designs with time-to-event endpoints. Most recently I have shifted the primary focus to early phase clinical trials, yet I am still trying to keep up with all the new development in the field. I love reading, traveling and photography during the leisure time. So far I have visited some fantastic places and hopes to visit more in the future.

3 Sharma V, McNeill JH (2009) To scale or not to scale: the principles of dose extrapolation. Brit J Pharmacol, 157(6):907–21


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