OnCo
ideasIdea

Mechanistic computer models to pick combination doses before dosing patients

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.

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.

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.
What would test it
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
Who has to act
industry
Cost to try
Medium ($1M to $50M)
Years to first evidence
3
Bottlenecks it attacks
  • Too many combinations to test · There are thousands of possible drug pairs and sequences. Trials can test a few dozen a year.
  • Wrong doses · Most drug doses were chosen as the highest a person can tolerate, which is often more than they need.

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