(M-053) Exploratory population pharmacokinetic analysis of vixarelimab using a two-target quasi-steady-state TMDD model in healthy volunteers and patients with pruritic conditions

Fei Tang – Clinical Pharmacology – Genentech; Steve Dang – Clinical Pharmacology – Genentech; Audrey Arjomandi – Bioanalytical Sciences – Genentech; Smita Kshirsagar – Clinical Pharmacology – Genentech; Lin Pan – Clinical Pharmacology – Genentech; Joy Hsu – Clinical Pharmacology – Genentech; Nastya Kassir – Clinical Pharmacology – Genentech

Objectives: Vixarelimab (KPL-716) is an investigational first-in-class fully human monoclonal antibody targeting oncostatin M receptor beta (OSMRβ) [1]. The objective of this work was to develop a population target-mediated drug disposition (TMDD) model that simultaneously characterizes the pharmacokinetics (PK) of vixarelimab and total soluble OSMR (sOSMR) in healthy volunteers and patients with pruritic conditions.

Methods: Vixarelimab PK data from three clinical studies were used: KPL-716-C001 (Phase 1 study in healthy volunteers and patients with atopic dermatitis), KPL-716-C201 (Phase 2a/b study in patients with prurigo nodularis), and KPL-716-C202 (Phase 2 study in patients with chronic pruritic diseases). Total sOSMR data were available from a subset of patients during sOSMR assay qualification. Model development evaluated a standard 2-compartment TMDD model with quasi-steady-state (QSS) assumption versus a 2-compartment two-target TMDD QSS model incorporating a Michaelis-Menten elimination term describing drug elimination through binding to membrane-bound OSMR (mOSMR) [2]. Models were implemented in NONMEM using first-order conditional estimation with interaction (FOCEI). Evaluation criteria included diagnostic plots, relative standard errors, and parameter plausibility.

Results: The dataset included 4050 PK observations from 274 subjects, and 253 total sOMSR observations from 54 subjects. While both models described the PK data well, the two-target TMDD QSS model significantly improved the fit to sOSMR data and demonstrated a lower Akaike Information Criterion (AIC). Among covariates tested, body weight significantly influenced clearance and central volume and was incorporated using estimated allometric exponents. The final model provided a good fit to both PK and sOSMR data, with good parameter precision.

Conclusions: A two-target QSS TMDD model effectively described the pharmacokinetics of vixarelimab and its binding to both soluble and membrane-bound OSMR. This model supports robust exposure and target level predictions and may inform dose selection and translational strategies for similar therapeutic antibodies.

Citations: [1] Sofen H, Bissonnette R, Yosipovitch G, Silverberg JI, Tyring S, Loo WJ, Zook M, Lee M, Zou L, Jiang GL, Paolini JF. Efficacy and safety of vixarelimab, a human monoclonal oncostatin M receptor β antibody, in moderate-to-severe prurigo nodularis: a randomised, double-blind, placebo-controlled, phase 2a study. EClinicalMedicine. 2023 Feb 3;57:101826.
[2] Gibiansky L, Gibiansky E. Target-mediated drug disposition model for drugs that bind to more than one target. J Pharmacokinet Pharmacodyn. 2010 Aug;37(4):323-46.

Keywords: Population pharmacokinetics, target-mediated drug disposition, multi-target binding