Workshop 2025: Chasing optimum First-in-Human dose | Welcome to reality !

09h00-09h15

Welcome Coffee

09h15-09h30

Introduction | Round Table

9h30-10h30

Getting the FIH dose right : how to transform preclinical knowledge into clinical applications

Antoine Deslandes, Sanofi

First-in-human (FIH) trials serve as critical milestones, bridging the gap between preclinical studies and subsequent clinical development phases. These trials primarily aim to establish a safe dose range for further clinical development. Regulatory guidelines outline a structured framework that includes: characterization of pharmacological and toxicological effects in vitro and in animal models, prediction of human exposure, anticipation of human response, and mitigation of potential risks from unknowns and uncertainties. Consequently, selecting an FIH dose necessitates the integration of data from multiple disciplines. Despite the differences between biologics (such as monoclonal antibodies) and small molecules, the fundamental principles for determining an FIH dose remain similar. These principles can be categorized into model-independent and model-based approaches

10h30-12h30

Physiologically Based PharmacoKinetics (PBPK) modelling to support the First In Human (FIH) studies of small molecules 

François Bouzom, Simulations Plus

In this section of the workshop, the attendees will learn about the value of the PBPK approach to support FIH studies using decision trees to better define the absorption, the distribution, the metabolism and the excretion of the drugs in development.

The strategy will be illustrated with a couple of case studies.

Finally, a hands-on session will allow each attendee to apply the strategy to a case study.

12h30-13h30

On-site buffet Lunch

13h45-14h00

Q&A morning session

14h00-15h00

Working with Probability of Pharmacological Success (PoPS) to inform FIH studies

Martin Bergstrand, Pharmetheus

The Probability of Pharmacological Success, or PoPS, is a metric to inform early-stage drug development decisions based on benefit and risk data available at the time. In a FIH setting PoPS can for example be used to: (1) prioritize between different candidate assets to decide which one to bring into clinic and (2) select the planned dose range to study in FIH studies.

The PoPS approach was initially introduced by Dr. Chao Chen and colleagues. The approach leverages information about pharmacokinetics (PK), exposure–response (ER) relationships for desired as well as undesired pharmacology (efficacy and safety). In addition, it defines targets for the relevant endpoints (e.g. target engagement and risk of exposure above the no observed adverse effect level). At the stage of FIH the available PKPD information about is usually primarily based on in vitro and/or animal studies. These are by nature associated with considerable uncertainty. PoPS allows to account for this uncertainty in a quantitative manner, and to propagate it them into an overall probability to meet a multi criteria definition of pharmacological success.

Pharmetheus has extended the original PoPS concept and implemented a template workflow to facilitate efficient and reproducible applications. The template workflow was developed for RStudio and Quarto to allow for a combination of ease of use for simple routine applications and more advanced custom applications.

The presentation will introduce the basic idea of PoPS as well as the template workflow in application to a FIH case-study. For confidentiality reasons this will be a simulated hypothetical example inspired by real case studies. It will also discuss the importance of systematically accounting for uncertainties in planning for FIH studies and the value of a workflow that can be easily updated with emerging information during early drug development.

15h00-17h00

Knowledge sharing on specific challenges for FIH dose predictions

Glenn Gauderat, Servier

This session will be dedicated to informal discussions around technical and strategic topics related to FIH dose predictions. From dose selection rationales to translational PK/PD methods.

Each topic will be introduced by a dedicated speaker, then the topic will be discussed with attendees to share practices and viewpoints.

• Prediction of antibody exposure at site of action : healthy tissues and tumors
• hFcRn mice models for FIH PK predictions
• Prediction of subcutaneous bioavailability for antibodies
• FIH estimation for 3 case studies & retrospective analysis from clinic

17h00-17h15

Survey-Wrap-up