Describe a TMDD (target-mediated drug disposition) situation and how it can produce nonlinear PK.

• A. A drug with low affinity receptors shows straight-line PK
• B. A drug with a high-affinity receptor shows saturable binding and clearance; clearance decreases as concentration increases
• C. Clearance increases without bound at high doses
• D. PK becomes strictly dose-proportional

Answer: (B)

Target-mediated drug disposition happens when a drug binds tightly to a finite biological target (like a receptor) that itself contributes to the drug’s clearance. Because there are only so many target molecules, binding and clearance via this pathway can become saturated. At low concentrations, a large fraction of the drug is cleared through the target pathway, so clearance can be relatively high and highly concentration-dependent. As the dose increases and receptors become saturated, this target-mediated clearance cannot keep up, effectively decreasing the clearance contributed by the target route. The remaining, non-target clearance pathways are slower and more constant, so the overall clearance falls and exposure rises more than proportionally with dose. This saturation of the high-affinity, target-related clearance is what produces nonlinear PK.