Modeling and Simulation of the Pharmacokinetics and Target Engagement of an Antagonist Monoclonal Antibody to Interferon‐γ–Induced Protein 10, BMS‐986184, in Healthy Participants to Guide Therapeutic Dosing

Abstract

BMS-986184 is a human, second-generation, anti-interferon-γ-induced protein 10 (IP-10) monoclonal antibody. In this study the pharmacokinetics and target engagement (TE) of BMS-986184 in healthy participants were characterized using population-based target-mediated drug disposition (TMDD) modeling and data from a first-in-human study (NCT02864264). The results of the first-in-human study and the model generated were used to conduct stochastic simulations of a virtual population of healthy participants to predict pharmacokinetic exposures and TE responses for different dosage regimens. A 2-compartment, 2-target, TMDD structural model, assuming quasi-steady-state and stimulated production on treatment, was developed by simultaneous fitting of the total drug, serum-free IP-10, and serum total IP-10 concentration data, with the second unobservable target contribution to drug elimination described by the Michaelis-Menten elimination term. Model evaluation confirmed agreement between model predictions and observed data. Simulation of a virtual population of healthy individuals demonstrated that steady state was reached at the eighth dosing interval, and that around 150 mg subcutaneously every other week could be a suitable target dosage regimen for future clinical trials.Integrated modeling strategies such as this can be used to help guide rational clinical trial development of drugs with TMDD, leading to improved dose selection and greater patient benefits.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Additional supplemental information can be found by clicking the Supplements link in the PDF toolbar or the Supplemental Information section at the end of webbased version of this article.

Serum and Urine Interferon Gamma-Induced Protein 10 (IP-10) Levels in Lupus Nephritis

“…The primary and secondary endpoints were not met, but higher doses were associated with increased clinical response and histological improvements, and treatment was determined to be safe. A promising second-generation human IP-10 monoclonal antibody (BMS-986184) has also been developed [ 28 ].…”

Reinventing Therapeutic Proteins: Optimizing Investments and Meeting Humanitarian Needs

“…160 A PK and target engagement (molecular interaction) study of anti-interferon-γ-induced protein 10 (IP-10) mAb was characterized, which concluded optimal dose strategy and scheduling of drug administration, i.e., approximately eight subcutaneously delivered dose intervals were required weekly in this case to reach steady state. 161 Specialized cell-based bioassays or potency assays, including ELISA, binding assays, competitive assays, cell signaling, ligand binding, proliferation, and proliferation suppression, are essential in ascertaining the mechanism of action and similarity with the parent molecule. On the other hand, functional tests related to the possible MOA, such as apoptosis, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and antibody-dependent cellular cytotoxicity, among others, are necessary but not essential and also when it is not relevant.…”