Translational PK/PD and model-informed development of JNJ-67842125, a F reversal agent for JNJ-64179375, a long-acting thrombin inhibitor.

BACKGROUND AND PURPOSE

Antigen-binding fragment (F ) reversal agents were developed to reverse, in bleeding emergency, the long-acting anticoagulant effect of JNJ-64179375 (JNJ-9375), a monoclonal antibody that binds exosite-1 on thrombin.

EXPERIMENTAL APPROACH

The pharmacokinetic and pharmacodynamic (PK/PD) activities of three reversal agents of varying in vitro binding affinities to JNJ-9375 were characterised in cynomolgus monkeys. The time course of JNJ-9375 anticoagulant activity and reversal effects of each agent were evaluated. A mechanism-based PK/PD model, which integrated free serum concentrations of reversal agent, total and free serum concentrations of JNJ-9375, and thrombin time, was developed to quantitatively relate JNJ-9375 neutralisation to reversal of induced thrombin time prolongation. Model-based allometric scale-up of the lead reversal agent and the PK/PD relationship of JNJ-9375 in healthy volunteers were utilised to predict clinical dosing regimens.

KEY RESULTS

Lowering of free JNJ-9375 by the reversal agents corresponded with reversal of thrombin time prolongation. Total JNJ-9375 displayed typical mAb clearance at 2.75 ml·day ·kg , whereas reversal agents cleared faster between 1400 and 2400 ml·day ·kg . The model-estimated in vivo K values for JNJ-9375 reversal agents 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 reversal agents exhibited different neutralisation 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.

CONCLUSION AND IMPLICATIONS

The results enabled selection of JNJ-67842125 as the reversal agent for JNJ-9375.