Target Residence Time: The Hidden Driver of In Vivo Efficacy
- Terry's Desk
- Aug 19
- 3 min read
Kenakin’s latest lecture delivers a paradigm shift for pharmacologists working on drugs where in vitro potency fails to predict clinical outcomes. If your lead compounds look perfect on paper but disappoint in vivo, residence time may be the missing piece.
This course redefines what makes a drug “effective,” arguing that kinetic persistence (not binding affinity) determines real-world success. From restricted tissue diffusion to PK–PD dissociation, Kenakin equips you with the kinetic models and biological context needed to design drugs that actually work where it matters: in the body.
In This Session, You’ll Gain:
✅ Modeling tools to understand how restricted diffusion in tissues like tumors slows offset and improves therapeutic window
✅ Examples of how rebinding in dense receptor environments amplifies target occupancy, even post-clearance
✅ Insight into why half-life can be misleading when volume of distribution hides the drug from its target
When Potency Isn’t Enough
Drug discovery teams are trained to chase nanomolar potency. But this metric assumes equilibrium, and equilibrium doesn’t exist in vivo. Concentrations rise and fall. Clearance happens. And drugs only work when they’re bound.
Kenakin walks through cases where two equipotent ligands produce radically different clinical outcomes, not because of potency, but because of how long they stay on target. In a world of fluctuating drug levels, residence time becomes the true predictor of effect.
Diffusion, Rebinding, and Receptor Density: The In Vivo Edge
This lecture shows how tissue architecture alters drug action. In structured, diffusion-restricted environments (e.g. brain, tumors), drugs don't just leave slowly; they often rebind. And when receptors are dense (like GPCRs on membranes), this rebinding hits the collisional limit, where every molecular encounter leads to binding.
The result? Drugs with poor pharmacokinetics can outperform flashier compounds by exploiting kinetic environments that weren’t visible in vitro assays.
PK–PD Dissociation: When Clearance Doesn’t Mean It’s Over
The lecture’s standout example: Aplaviroc, an allosteric CCR5 inhibitor with rapid systemic clearance—yet near-permanent occupancy at its target. The takeaway is clear: fast clearance does not necessarily mean loss of efficacy when binding offset is slow.
This has implications for everything from dosing frequency to resistance barriers in infectious disease and oncology.
Why Half-Life Can Lie to You
Most teams use systemic half-life as a proxy for action. But as Kenakin shows, t½ is a surface metric—a combination of clearance and volume of distribution. A drug hiding in fat tissue may stay in the body for days, but if it never reaches the target site, the therapeutic effect is zero.
He breaks down how to distinguish between true target persistence vs. sequestration, with clear takeaways for decision-making in lead optimization and formulation.
Rebuild Your Metrics. Redefine Your Pipeline
If your development program is built around potency alone, you may be leaving high-value compounds behind. Residence time provides a second dimension of drug evaluation, one that explains results in animal models, informs clinical translation, and helps teams avoid late-stage surprises.
Kenakin offers not just theory, but tools to model, predict, and validate this behavior early.
Why Terry’s Corner
In a world where drug discovery is evolving faster than most can track, Terry’s Corner is your shortcut to staying ahead.
Here’s what members get:
Weekly deep dives from Dr. Terry Kenakin
Monthly Ask‑Me‑Anything sessions with live Q&A
An expanding on‑demand library for novices to expert drug hunters
Influence over future topics
Access to the study group
Whether you’re in hit-to-lead, lead optimization, or clinical pharmacology strategy, this is where 40 years of kinetic expertise meet the real questions you’re asking in the lab.
Don’t just keep pace—outpace the field.
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