Illustrative activation model
Hold liver activation steady; test the systemic leak
An illustrative hepatic-activation calculation separates two design levers. Hold hepatic extraction at 50% and productive liver activation at 80%. Compare a prodrug with 80% systemic activation against one with 20%, while keeping the other assumptions fixed.
- 0.40 → 0.40Active generated in liver
0.50 extracted × 0.80 productively activated.
- 0.40 → 0.10Active generated systemically
0.50 escaping × 0.80 or 0.20 activated.
- ≈1:1 → ≈4:1Ratio of active generation
The change comes from lower systemic activation.
- Read the two amounts before ranking the ratio · The second scenario preserves modeled liver activation while reducing active drug generated after escape. Whether that trade is useful depends on where the target needs active drug. Measure liver and plasma conversion separately before using this hypothesis to select chemistry.
- Keep GalNAc uptake as a separate question · Published GalNAc-siRNA work demonstrates hepatocyte delivery for those constructs. It does not supply a universal uptake multiplier for a small-molecule conjugate. A GalNAc strategy needs construct-specific receptor uptake, release and compartment-exposure evidence.
- Use the familiar model for the decision it can support · This is a bounded fraction-balance calculation, alongside standard hepatic extraction modeling. BioTwin’s useful connection is to carry the liver and systemic assumptions into the intervention assessment. Clearance, distribution and exposure over time still require calibration.
Two routes, two sets of measurements
GalNAc targeting investigates receptor-mediated uptake into hepatocytes. Hepatic activation investigates conversion during passage through the liver and the resulting hepatic and systemic exposure. A targeting label alone cannot answer the activation question, and an extraction model cannot establish receptor-mediated uptake.
Match the model to the intervention
The current toolkit contains distinct uptake and hepatic-activation operations. Use the one that fits the molecule, administration route and target compartment. Each requires its own parameters and calibration; evidence for one construct does not transfer automatically to another.
Make the delivery question affect the design
For a supplied GalNAc-containing clearance construct, receptor recruitment belongs alongside target binding and uptake. For an activation strategy, conversion and systemic escape may instead decide the experiment. A program can compare these hypotheses without pretending they are the same delivery mechanism.
- Extracellular clearance · Review the scope of ASGPR-LYTAC construct composition. Extracellular clearance
- Activation rules · Specify the biological conditions a proposed drug should require. Activation rules
- Exposure models · Investigate the compartment and time-course assumptions. Exposure models