Mechanism-based modeling of the effect of a novel inhibitor of vascular adhesion protein-1 on albuminuria and renal function markers in patients with diabetic kidney disease.

Abstract

The vascular adhesion protein-1 (VAP-1) inhibitor ASP8232 reduces albuminuria in patients with type 2 diabetes and chronic kidney disease. A mechanism-based model was developed to quantify the effects of ASP8232 on renal markers from a placebo-controlled Phase 2 study in diabetic kidney disease with 12 weeks of ASP8232 treatment. The model incorporated the available pharmacokinetic, pharmacodynamic (plasma VAP-1 concentration and activity), serum and urine creatinine, serum cystatin C, albumin excretion rate, urinary albumin-to-creatinine ratio, and urine volume information in an integrated manner. Drug-independent time-varying changes and different drug effects could be quantified for these markers using the model. Through simulations, this model provided the opportunity to dissect the relationship and longitudinal association between the estimated glomerular filtration rate and albuminuria and to quantify the pharmacological effects of ASP8232. The developed drug-independent model may be useful as a starting point for other compounds affecting the same biomarkers in a similar time scale.

• Authors: Sven Hoefman, Nelleke Snelder, Martijn van Noort, 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. 21-38 (02 2021) ISSN: 1573-8744 [Electronic] United States
• PMID: 32929612 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Administration, Oral
• Aged
• Albuminuria (blood, drug therapy, etiology)
• Amine Oxidase (Copper-Containing) (antagonists & inhibitors, metabolism)
• Biomarkers (blood, urine)
• Cell Adhesion Molecules (antagonists & inhibitors, metabolism)
• Clinical Trials, Phase II as Topic
• Computer Simulation
• Diabetic Nephropathies (blood, drug therapy, urine)
• Glomerular Filtration Rate (drug effects, physiology)
• Humans
• Kidney (drug effects, physiopathology)
• Male
• Models, Biological
• Organic Chemicals (pharmacology, therapeutic use)
• Randomized Controlled Trials as Topic