Target-Mediated Drug Disposition

Overview

Pharmacokinetic phenomenon where antibody binding to its target accelerates systemic clearance, creating a paradox for anti-TFPI antibodies where improving binding affinity worsens PK; resolved for mastacimab via mechanistic PK/PD modeling that identified a moderate nanomolar affinity at 100 mg weekly as sufficient. Anti-TFPI antibodies are cleared from circulation much more rapidly when they bind their target; at very high doses (10 mg/kg) TMDD is saturated and PK normalizes, but at therapeutic doses the rapid clearance dominates and antibodies have very short effective half-lives. Improving anti-TFPI antibody binding affinity paradoxically worsened clearance: low-affinity antibodies exhibited normal clearance while progressively higher affinity led to progressively faster elimination, making the standard drug optimization approach counterproductive. (TMDD Challenge (30:00-35:00))