title: Population pharmacokinetic and pharmacodynamic modeling of MNRP1685A in cynomolgus monkeys using two-target quasi-steady-state (QSS) model.
abstract: MNRP1685A (anti-NRP1) is a fully human IgG1 monoclonal antibody against neuropilin-1 (NRP1), a protein necessary for blood vessel maturation. MNRP1685A binds to free membrane-bound NRP1 (mNRP1) and circulating NRP1 (cNRP1). Total cNRP1 increased in a dose-dependent manner following anti-NRP1 administration in mice, rats, and monkeys. The purpose of this study is to develop a mechanism-based model to simultaneously describe the kinetics of both unbound drug (MNRP1685A) and total cNRP1 in cynomolgus monkeys. Pharmacokinetic (PK) and pharmacodynamic (PD) profiles after single- or multiple-dose administrations were well described by the two-target quasi-steady-state (QSS) model. The estimated nonspecific clearance was 3.26 mL/day/kg and central compartment volume was 38.2 mL/kg. The maximum elimination rate for mNRP1-mediated disposition was 98.8 nM/day. The synthesis rate (3.8 nM/day), degradation rate constant (1.53 day(-1)), and complex elimination rate constant (0.260 day(-1)) for cNRP1 were also derived from the model. QSS constants were 6.94 nM for mNRP1 and 2.8 nM for cNRP1. The results suggest that cNRP1 has minimal effect on MNRP1685A PK while mNRP1 plays a major role in the target-mediated drug disposition. This finding is favorable as the desired pharmacological target is mNRP1, rather than cNRP1. The two-target QSS model provides mechanistic understanding of the nonlinear PK of MNRP1685A. Based on the model prediction, the free drug concentrations to maintain free mNRP1 and cNRP1 below 10% of baseline level are 10 and 20 μg/mL, respectively. This serves as a target concentration for clinical dose selection, assuming cynomolgus monkeys are predictive for humans.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics, Genentech Research and Early Development, Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xin
authors.forename: Hong
authors.initials: H
authors.lastname: Xiang
authors.forename: Denise
authors.initials: D
authors.lastname: Jin
authors.forename: Frank-Peter
authors.initials: FP
authors.lastname: Theil
authors.forename: Amita
authors.initials: A
authors.lastname: Joshi
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Damico-Beyer
authors.forename: Shuang
authors.initials: S
authors.lastname: Bai
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D008954:Models, Biological; D039942:Neuropilin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010599:Pharmacokinetics; D012756:Sheep
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D039942:Neuropilin-1