# Mechanistic computer models to pick combination doses before dosing patients

Source: https://onco.cc/ideas/idea-tr2-qsp-combo-dosing/  
OnCo record `idea-tr2-qsp-combo-dosing` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Simulate how two drugs interact in the body and the tumour to pick a starting dose and schedule, instead of guessing from single-drug data.

## Summary

Quantitative systems pharmacology models integrate pharmacokinetics, target engagement and downstream biology to predict combination effects and toxicities. FDA's model-informed drug development pathway accepts such models for dose justification. Making a QSP-based schedule proposal a standard component of combination investigational new drug applications would reduce empirical dose-escalation in combinations.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: Combination trials whose dose and schedule were selected with a pre-specified QSP model will require fewer dose-escalation cohorts and reach recommended phase 2 dose with fewer dose-limiting toxicities than trials using conventional escalation.
- Rationale: QSP models predicted the therapeutic window of several bispecifics and ADCs; overlapping toxicity in combinations is largely predictable from pharmacology.
- Proposed test: Retrospectively apply QSP dose selection to ten completed combination phase 1 trials and compare predicted with observed recommended doses; then run prospectively in five new trials.
- Maturity: early-clinical
- Actor: industry

## Sources

- FDA model-informed drug development programme: https://www.fda.gov/drugs/development-resources/model-informed-drug-development-paired-meeting-program

## Connected records

- ideas: [Find the lowest effective doses of both drugs in a combination, not the highest tolerated](https://onco.cc/ideas/idea-tr2-combo-dose-matrix/)
- technologies: [AI-driven drug & target discovery](https://onco.cc/technologies/ai-drug-design/)
- bottlenecks: [Too many combinations to test](https://onco.cc/bottlenecks/b-combination-space/), [Wrong doses](https://onco.cc/bottlenecks/b-dose-optimisation/)

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