FIH for Biologics with Immunogenicity Assessment

Accurate prediction of first-in-human (FIH) dose for biologicals such as monoclonal antibodies (mAbs), therapeutic proteins and bi/multi-specifics requires consideration of various features that determine the clinical PK properties of such modalities, including target-mediated drug disposition (TMDD) and immunogenicity (IG) caused by anti-drug antibodies (ADAs). Further, given the advent of highly active biotherapeutics that can induce serious toxicities including cytokine release syndrome and neurotoxicity at low doses, there is a move towards using FIH starting doses based on anticipated biological effects rather than conventional preclinical safety margins.
The Simcyp FIH Biological platform has been designed to take into account these complex mechanisms in an efficient manner to enable a robust FIH dose prediction based on readily available preclinical input data, leveraging our unique QSP platform.

This approach integrates preclinical mechanistic evidence and physiological system models to investigate and predict human PK of biotherapeutics.

Focus on Immunogenicity (IG)

As defined by the US FDA, IG is the propensity of a therapeutic product to generate immune responses to itself , or to induce certain immunologically related adverse clinical events. This can be exacerbated when administered as multiple doses over prolonged periods. Administration of biotherapeutics frequently triggers immunogenic responses in patients in the form of ADAs, which may affect PK and thus drug efficacy. The immunogenic response generally includes both (T cell) and (antibody) arms of the immune response.

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Focus on Immunogenicity (IG)
Immunogenicity Risk Assessment Using Certara’s IG Simulator

Immunogenicity Risk Assessment Using Certara’s IG Simulator

Certara’s IG Risk Assessment product leverages the proprietary IG Simulator
to predict and manage IG in a specific development program, and guide design of potential novel molecules. The IG Simulator can not only predict IG incidence, but uniquely also the impact on PK and how this is influenced by the dosing regimen.

An initial IG Risk Assessment can be determined with very little data – the structure of the protein alone is all that is needed for a first in silico prediction. Additional in vitro and in vivo data can be integrated in subsequent steps. The IG Risk Assessment will guide critical decision-making around compound selection, human prediction and design of phase 1 studies.

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