Mechanism-based modeling of the effect of a novel inhibitor of vascular adhesion protein-1 on albuminuria and renal func
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ORIGINAL PAPER
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 Hoefman1 • Nelleke Snelder1 • Martijn van Noort1 • Alberto Garcia-Hernandez2 • Hartmut Onkels2 Tobias E. Larsson2 • Kirsten R. Bergmann2
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Received: 19 November 2019 / Accepted: 1 September 2020 Ó The Author(s) 2020
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. Keywords VAP-1 inhibition Albuminuria Mechanism-based modeling Abbreviations AER Albumin excretion rate ALBUM ASP8232 phase 2 trial in DKD patients: ClinicalTrials.gov NCT02358096 BSA Body surface area CI Confidence interval CR EGFR CysC circadian rhythm component Cu Individual ASP8232 plasma concentrations not bound to VAP-1 DKD Diabetic kidney disease eGFR Estimated glomerular filtration rate
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10928-020-09716-x) contains supplementary material, which is available to authorized users. & Sven Hoefman [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
ER FMV IIV NLME OFV PI PK-PD Qd RSE sCr sCysC T, TAFD Tclock TV UACR uCr Uvol VAP-1 VPC g h
Exposure–response First morning void Inter-individual variability Non-linear mixed effects Objective function value Prediction interval Pharmacokinetic-pharmacodynamic Once daily dosing Relative standard error Serum creatinine Serum cystatin C Time after first dose in hours Clock time Typical value Urinary albumin-to-creatinine ratio Urine creatinine Urine volume Vascular adhesion protein-1 Visual predictive check Random effect for inter-individual variability Fixed effect model parameter
123
Journal of Pharmacokinetics and Pharmacodynamics
List of PK model parameters (THETA number, hn, reflects the number of the parameters in Table 1 and
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