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

Sven Hoefman,Martijn Van Noort,Alberto Garcia-Hernandez,Nelleke Snelder,Kirsten R Bergmann,Hartmut Onkels,Tobias E Larsson

doi:10.1007/s10928-020-09716-x

Sven Hoefman, Martijn Van Noort + Show 5 more

Open Access

https://doi.org/10.1007/s10928-020-09716-x

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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.

Highlights

Albuminuria is a surrogate marker of progression of chronic kidney disease and a reduction of albuminuria is associated with improvements in long-term clinical outcomes, such as end-stage renal disease
The scale factor, h scale, between albumin excretion rate (AER) and urinary albumin-to-creatinine ratio (UACR) in Eq 1 significantly improved the model fit (DOFV = - 19), and it was kept in the model
The link between AER and estimated glomerular filtration rate (eGFR) CysC was well described by a proportional linear function (Eq 4), whereas the link between serum creatinine (sCr) and eGFR CysC was best described by a polynomial function (Eq 5)

Summary

Introduction

Albuminuria is a surrogate marker of progression of chronic kidney disease and a reduction of albuminuria is associated with improvements in long-term clinical outcomes, such as end-stage renal disease. Following a 12-week treatment period with 40 mg qd ASP8232, the primary and key secondary endpoints indicated a 20% reduction in 24-h urinary albumin concentrations and a 19.5% reduction in first morning void (FMV) urinary albumin-to-creatinine ratio (UACR) versus placebo, respectively. These effects were thought to result from the near-complete inhibition of VAP-1 activity during treatment. Soluble VAP-1 levels are increased in subjects with diabetes and early stages of chronic kidney disease, and its oxidase activity is expected to play a pathogenic role in DKD patients [4,5,6,7]

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