November 14, 2025
Preclinical QSP models: support for early decision making
Preclinically, targeted radiotherapies are evaluated in mouse PK studies, xenograft models, and biodistribution studies to characterize uptake and accumulation of radioactivity in tumors and healthy organs. These experiments are often limited to a few time points (e.g., 2-4 measurements over 24-48 hours), constraining interpretation of drug behavior. QSP modeling helps bridge these gaps by guiding study design, supporting translation to other model systems, and improving understanding of dose–response relationships.
Applications of QSP modeling in targeted radiotherapies development
The following examples illustrate how QSP approaches can guide lead selection, target evaluation, and dose optimization in preclinical targeted radiotherapies development.
Binding affinity and tumor uptake
Key questions:
- How should we define our Target Product Profile (TPP) for a given receptor target and carrier/isotope combination?
- Does our current lead achieve maximal tumor uptake, or is further affinity maturation needed?
Simulations across a range of binding affinities reveal whether a targeted radiotherapy binds too weakly to achieve meaningful targeting or, conversely, whether affinity maturation has reached a point of diminishing returns. In this case, improvements beyond sub-nanomolar KD values yielded only marginal gains in tumor uptake, insights that can guide rational optimization of targeted radiotherapy design.
Target properties and tumor delivery
Key questions:
- Will the expression and turnover profile of our target receptor deliver sufficient radioactivity to the tumor?
- How should we design preclinical studies with new tumor lines?
Simulations exploring receptor internalization rates and expression levels help predict which targets may yield suboptimal tumor activity. Slower internalization and lower receptor density limit delivery of active drug to tumors; QSP modeling provides quantitative comparisons to select the most promising targets. In practical applications, these models also support study design—from preclinical biodistribution through Phase 1 dosimetry.
Mass/activity balance and therapeutic index
Key questions:
- What dosing regimen will give the best safety window?
- Can we spare healthy tissues while maintaining effective tumor dosing?
At low mass doses, off-tumor uptake of radioligand can yield an unfavorable therapeutic index. Increasing the mass dose can reduce healthy-tissue uptake by saturating off-tumor receptors with cold drug—but may also reduce tumor uptake. QSP models can identify the “sweet spot,” where the mass-to-activity ratio maximizes tumor-to-normal tissue exposure and assess whether that therapeutic window is sufficiently wide. These analyses help interpret otherwise non-intuitive preclinical findings.
Model-Informed Drug Development Framework for the Development and Dose Optimization of Targeted Radiation Therapies
Explore our end-to-end framework for using MIDD with TRTs, specifically with PSMA targeting radio-ligands, in this poster.
Senior Director, QSP
Joshuaine Grant is a Senior Director in Quantitative Systems Pharmacology at Certara with more than 25 years of experience integrating biophysics, disease biology, and quantitative modeling to advance drug development. She leads collaborative projects that use mechanistic and translational QSP modeling to inform key decisions from discovery through the clinic. Her broad experience across biologics and complex therapeutics has supported Certara’s growing leadership in radioligand and targeted radiotherapies.
Sr Scientist, QSP
Sarah Minucci is a QSP modeler with a background in applied mathematics and systems biology. She guides strategy and builds fit-for-purpose models to support drug development from early feasibility to first-in-human studies. Specializing in biologics, she has helped to spearhead modeling best practices for targeted radiopharmaceuticals at Certara and continues to advance Certara’s QSP targeted radiopharmaceuticals knowledge repository.
FAQs
At what stage of development for targeted radiopharmaceuticals can QSP modeling be used?
QSP modeling can be used at any stage, from discovery to the clinic. At early stages, QSP modeling can inform optimal drug and target properties and carrier/ligand combinations. It can also help design biodistribution studies and explore mass dose/activity balances in preclinical species. Finally, QSP modeling aids in translating preclinical insights into first-in-human dose justification and study design. QSP modeling builds confidence and reduces uncertainty in accelerating targeted radiotherapy development from bench to bedside.
What are the key benefits of using QSP modeling for targeted radiotherapies compared to traditional methods?
QSP modeling offers several benefits in the context of targeted radiotherapies:
- It mechanistically links receptor kinetics, radionuclide decay, carrier metabolism, and tissue distribution.
- It enables the exploration of “what-if” scenarios (e.g., different binding affinities, receptor densities, tumor sizes) to optimize lead selection.
- It helps predict tumor vs healthy organ exposure (therapeutic index) and thus supports dose optimization and risk-benefit assessment.
- It improves the translational bridge from animal to human by modeling species-specific biology and kinetics rather than relying solely on body-weight scaling or empirical rules.
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