PK/PD and target engagement
Minimal PK/PD models link concentration to a pharmacodynamic response (warfarin prothrombin complex activity, ER degradation by a PROTAC, RAS-pathway inhibition) and ask how effect delay, target turnover and exposure at the site of action change comparisons of dosing frequency.
When does individual information improve PK/PD prediction?
A reanalysis of measured warfarin PK/PCA data: effect delay, subject-separated prediction, and the limits of using additional PK measurements.
- In 32 subjects with public single-dose warfarin PK and PCA data, a turnover model described the delay between concentration and response better than direct inhibition (held-out RMSE 0.0799 vs 0.1061 at the 24 h cutoff).
- Adding each subject's PK measurements up to 24 or 48 h did not improve later PCA prediction: paired MSE differences were +0.0015 (−0.0012 to 0.0043) and +0.0021 (−0.0026 to 0.0064).
- Concentration information does not recover individual PD sensitivity; the next informative experiment measures PD sensitivity or tests a repeat occasion, and nothing here supports a dose, INR target or bleeding-risk claim.
Can maximal degradation alone set the dosing interval of a targeted protein degrader?
A review of public ER-PROTAC data and a minimal model of how assumptions about site-of-action exposure and target recovery change comparisons of dosing frequency and PD metrics. The model is not fitted to the actual drug, and no clinical dose is proposed.
- In public data, end-of-study ER degradation with vepdegestrant was at least 94% at every dose while TGI ranged from 85% to 120%, and the 24-hour tumor/plasma ratio for ERD-1233 was 9.81; end-of-study PD and plasma concentration do not stand in for efficacy or tumor exposure.
- In an assumption-based minimal model with a 6 h target half-life, Q2D gave higher maximal degradation than QD (81.1% vs 73.7%) but a lower minimum (14.3% vs 48.4%) and mean (52.2% vs 63.8%).
- Recovery rate, required degradation and the interval for an actual drug cannot be set from public data; measuring effect-site exposure and target recovery up to the next dose may inform the decision more than another maximal-degradation point.