Population pharmacokinetics and pharmacodynamics of a novel vascular adhesion protein-1 inhibitor using a multiple-target mediated drug disposition model.

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.

• Authors: Nelleke Snelder, Sven Hoefman, Alberto Garcia-Hernandez, Hartmut Onkels, Tobias E Larsson, Kirsten R Bergmann
• Journal: Journal of pharmacokinetics and pharmacodynamics (J Pharmacokinet Pharmacodyn) Vol. 48 Issue 1 Pg. 39-53 (02 2021) ISSN: 1573-8744 [Electronic] United States
• PMID: 32930923 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ASP8232
• Cell Adhesion Molecules
• Organic Chemicals
• AOC3 protein, human
• Amine Oxidase (Copper-Containing)

Topics

• Administration, Oral
• Albuminuria (blood, drug therapy, etiology)
• Amine Oxidase (Copper-Containing) (antagonists & inhibitors, blood, metabolism)
• Biological Availability
• Biological Variation, Population
• Cell Adhesion Molecules (antagonists & inhibitors, blood, metabolism)
• Clinical Trials, Phase I as Topic
• Clinical Trials, Phase II as Topic
• Computer Simulation
• Diabetic Nephropathies (blood, drug therapy)
• Dose-Response Relationship, Drug
• Female
• Gastrointestinal Absorption
• Glomerular Filtration Rate (drug effects, physiology)
• Healthy Volunteers
• Humans
• Kidney (drug effects, physiopathology)
• Male
• Models, Biological
• Organic Chemicals (administration & dosage, pharmacokinetics)
• Randomized Controlled Trials as Topic
• Renal Elimination
• Tissue Distribution