Mechanistic Modeling for Small Molecules and Biologics

Per regulatory guidance, estimation of a first-in-human (FIH) dose is an essential element in clinical development. Selection of that starting dose in humans is a complex process—it must be low enough to be safe but high enough to avoid excessive dose escalations. Pharmacokinetics (PK) that leverage a mechanistic approach provide accurate predictions of human PK prior to phase 1 studies, resulting in significant cost and time savings of up to 6 months. Simcyp’s Physiologically based Pharmacokinetic Modeling (PBPK) and Quantitative Systems Pharmacology (QSP) mechanistic modeling are applied for the purpose of PK and dose prediction across drug discovery and development—beginning in the early stages prior to lead development where limited data are available—to the translational IND enabling stage. Simcyp’s PBPK and QSP modeling & simulation technologies provide a deeper understanding of the effect of physiological variables on PK, along with risk factors such as drug-drug interactions for small molecules and immunogenicity for biologics.

Simcyp PBPK FIH Service for Small Molecules FIH for Biologics with Immunogenicity Assessments

Simcyp PBPK FIH Service for Small Molecules

Per regulatory guidance, estimation of a first-in-human (FIH) dose is an essential element in clinical development. Selection of that starting dose in humans is a complex process—it must be low enough to be safe but high enough to avoid excessive dose escalations. Pharmacokinetic (PK)-guided approaches provide a more mechanistic rationale, providing accurate predictions of human PK prior to phase 1 studies, resulting in significant cost and time savings of up to 6 months. Physiologically-based Pharmacokinetic Modeling (PBPK) can be applied for the purpose of PK and dose prediction across drug discovery and development from the early stages prior to lead development where limited data are available, enabling the understanding of the effect of physiological variables or disease status on PK.

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Simcyp PBPK FIH Service for Small Molecules
FIH for Biologics with Immunogenicity Assessment

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.

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