Population Pharmacokinetic/Pharmacodynamic Modeling of Glenzocimab (ACT017) a Glycoprotein VI Inhibitor of Collagen-Induced Platelet Aggregation

Abstract

Glenzocimab (ACT017) is a humanized monoclonal antigen-binding fragment (Fab) directed against the human platelet glycoprotein VI, a key receptor for collagen and fibrin that plays a major role in thrombus growth and stability. Glenzocimab is being developed as an antiplatelet agent to treat the acute phase of ischemic stroke. During a phase I study in healthy volunteers, the population pharmacokinetics (PK) and pharmacodynamics (PD) of glenzocimab were modeled using Monolix software. The PK/PD model thus described glenzocimab plasma concentrations and its effects on ex vivo collagen-induced platelet aggregation. Glenzocimab was found to have dose-proportional, 2-compartmental PK with a central distribution volume of 4.1 L, and first and second half-lives of 0.84 and 9.6 hours. Interindividual variability in clearance in healthy volunteers was mainly explained by its dependence on body weight. The glenzocimab effect was described using an immediate effect model with a dose-dependent half maximal inhibitory concentration: Larger doses resulted in a stronger effect at the same glenzocimab plasma concentration. The mechanism of the overproportional concentration effect at higher doses remained unexplained. PK/PD simulations predicted that 1000-mg glenzocimab given as a 6-hour infusion reduced platelet aggregation to 20% in 100% of subjects at 6 hours and in 60% of subjects at 12 hours after dosing. Simulations revealed a limited impact of creatinine clearance on exposure, suggesting that no dose adjustments were required with respect to renal function. Future studies in patients with ischemic stroke are now needed to establish the relationship between ex vivo platelet aggregation and the clinical effect.

Keywords: ACT017; acute phase of ischemic stroke; anti-GPVI Fab; glenzocimab; population PK/PD.

Conflict of interest statement

M.M., L.R., Y.P. are consultants to Acticor. M.J.‐P. and P.B. are founders and consultants to Acticor. K.L. is an employee of Acticor‐Biotech.

© 2020 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Individual and median ex vivo platelet aggregation vs time (left). Individual and median ex vivo platelet aggregation vs glenzocimab plasma concentrations (right). Doses in milligrams.

Figure 2

Visual predictive check for glenzocimab plasma concentrations by dose. Empirical median (green line) and 90% prediction interval of the model for the median (blue area). Red circles indicate empirical medians outside of the model prediction interval. Observations as blue dots; observations below the limit of quantitation as red dots.

Figure 3

Covariate effects on glenzocimab clearance for the observed range of age, creatinine, and body weight in the phase I study. Solid red line represents clearance for a typical individual, and dotted lines 50%, 75%, 125%, and 150% of this value. Numbers show range. The full range of individual clearance estimates is shown in the lowest row.

Figure 4

Individual half maximal inhibitory concentration (IC50) estimates (mode of conditional distribution) on log10 scale vs dose with regression line.

Figure 5

Visual predictive check for ex vivo platelet aggregation by dose. Empirical median (green line) and 90% prediction interval of the model for the median (blue area). Red circles indicate empirical medians outside of the model prediction interval. Observations as blue dots.

Figure 6

Dashed red line indicates the target of 95% patients. A, Percentage of individuals achieving 20% platelet aggregation at 6 hours or 12 hours vs dose with the phase I infusion scheme. B, Percentage of individuals achieving 20% platelet aggregation at 12 hours vs dose with a 6‐hour vs 12‐hour infusion. C, Percentage of individuals achieving 20% platelet aggregation at 6 hours or 12 hours vs body weight for a 1000‐mg dose with the phase I infusion scheme.