objective: Antigen-binding fragment (F ) reversal agents (RAs) were developed to reverse, in situations of bleeding emergency, the anticoagulant activity of JNJ-64179375 (JNJ-9375), a monoclonal antibody that specifically binds exosite-1 on thrombin and functions as a long-acting anticoagulant. methods: The pharmacokinetic and pharmacodynamic (PK/PD) activities of three RAs with varying in vitro binding affinities to JNJ-9375 were characterized in cynomolgus monkeys. The time course of JNJ-9375 anticoagulant activity and reversal effects of each RA were evaluated. A mechanism-based PK/PD model, which integrated free serum concentrations of RA, total and free serum concentrations of JNJ-9375, and thrombin time (TT), was developed to quantitatively relate JNJ-9375 neutralization to reversal of JNJ-9375-induced TT prolongation. Model-based allometric scale-up of the lead RA and the PK/PD relationship of JNJ-9375 in healthy volunteers were utilized to predict clinical dosing regimens. results: Lowering of free JNJ-9375 by the RAs corresponded well with reversal of TT prolongation. Total JNJ-9375 displayed typical mAb clearance at 2.75 mL/day/kg whereas RAs cleared faster between 1400-2400 mL/day/kg. The model-estimated in vivo K values for JNJ-9375 RAs were 9 nM (ICHB-256), 0.4 nM (ICHB-281), and 13.7 pM (ICHB-164), in rank-ordered agreement of their K values determined in vitro. The three RAs exhibited different neutralization characteristics in vivo, governed primarily by their binding kinetics to JNJ-9375. The model predicted a priori free JNJ-9375 kinetics after dosing ICHB-164 (JNJ-67842125) and JNJ-9375 under a different regimen. conclusions: The results enabled selection of JNJ-67842125 as the RA for JNJ-9375.