Population pharmacokinetics and pharmacodynamics of a novel vascular adhesion protein-1 inhibitor using a multiple-targe
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ORIGINAL PAPER
Population pharmacokinetics and pharmacodynamics of a novel vascular adhesion protein-1 inhibitor using a multiple-target mediated drug disposition model Nelleke Snelder1 • Sven Hoefman1 • Alberto Garcia-Hernandez2 • Hartmut Onkels2 • Tobias E. Larsson2 Kirsten R. Bergmann2
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Received: 20 November 2019 / Accepted: 1 September 2020 Ó The Author(s) 2020
Abstract ASP8232 is a novel inhibitor of vascular adhesion protein-1 that was under evaluation for reducing residual albuminuria in patients with diabetic kidney disease. To characterize the pharmacokinetics (PK) of ASP8232 and its effect on vascular adhesion protein 1 (VAP-1) plasma activity and VAP-1 concentrations (pharmacodynamics, PD) in an integrated and quantitative manner, a target mediated drug disposition model was developed based on pooled data from four completed clinical trials with ASP8232 in healthy volunteers, and in patients with diabetic kidney disease and diabetic macular edema, respectively. In this model, the binding of ASP8232 to its soluble and membrane-bound target in the central and peripheral compartments were included. The model was able to adequately describe the non-linear PK and PD of ASP8232. The observed difference in PK between healthy volunteers and renally impaired patients could be explained by an effect of baseline estimated glomerular filtration rate on ASP8232 clearance and relative bioavailability. The relationship between ASP8232 concentration and VAP-1 inhibition was successfully established and can be applied to simulate drug exposure and degree of VAP-1 inhibition for any given dose of ASP8232 across the spectrum of renal function. Keywords VAP-1 inhibition Albuminuria Diabetic kidney disease Population pharmacokinetic modeling
Introduction Vascular adhesion protein-1 (VAP-1) is a 180 kDa transmembrane homodimeric glycoprotein [1, 2]. As an amine oxidase, it catalyzes the oxidation of amines to form aldehydes, hydrogen peroxide and ammonia. VAP-1 has both enzymatic and non-enzymatic activities, and plays an important role in leukocyte trafficking and adhesion [3–5]. Membrane bound VAP-1 (mVAP-1) can be cleaved by
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10928-020-09717-w) contains supplementary material, which is available to authorized users. & Nelleke Snelder [email protected] 1
LAP&P Consultants BV, Archimedesweg 31, 2333 CM Leiden, The Netherlands
2
Astellas Pharma Europe BV, Global Development, Sylviusweg 62, 2333 BE Leiden, The Netherlands
metalloproteinases and shed as soluble VAP-1 (sVAP-1). sVAP-1 concentrations increase at sites of inflammation and its upregulation and subsequent increased oxidase activity plays a role in many inflammatory diseases [6, 7]. sVAP-1 is upregulated in diabetic patients [8, 9] and subjects with early stages of chronic kidney disease [10], where VAP-1 activity is thought to play an important pathogenic role. ASP8232 is a small molecule VAP-1 inhibitor that was evaluated for the treatment of diabetic kidn
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