Translational PK/PD and model-informed development of JNJ-67842125, a F ab reversal agent for JNJ-64179375, a long-acting thrombin inhibitor
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. The pharmacokin...
Saved in:
Published in | British journal of pharmacology Vol. 178; no. 19; pp. 3943 - 3958 |
---|---|
Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
01.10.2021
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | 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.
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.
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.
The results enabled selection of JNJ-67842125 as the RA for JNJ-9375. |
---|---|
ISSN: | 0007-1188 1476-5381 |
DOI: | 10.1111/bph.15533 |