Jonathan Mochel (1, 4), Martin Fink (1), Mathieu Peyrou (2), Jerome Giraudel (3), Meindert Danhof (4)
(1) Novartis Pharma AG, Modeling & Simulation, CH-4002 Basel, Switzerland; (2) Novartis Centre de Recherche Santé Animale SA, CH-1566 Saint-Aubin, Switzerland; (3) Novartis Animal Health Australasia Pty Ltd, Research Centre, NSW 2178 Kemps Creek, Australia; (4) Leiden University Department of Pharmacology, 2300 RA Leiden, The Netherlands
Objectives: In the management of canine heart failure, angiotensin converting enzyme inhibitors (ACEIs) e.g. benazepril are the foremost therapeutic option to offset activation of the Renin-Angiotensin-Aldosterone System (RAAS) [1]. Only limited information on the effect of benazepril on circulating RAAS peptide levels is presently available in veterinary medicine. The objective of this research was to determine the effect of benazepril on the renin-angiotensin cascade using nonlinear mixed effects modeling. Chronobiology of RAAS biomarkers and determinants of their regulation were further investigated.
Methods: Blood specimens were collected from a group of 12 healthy beagle dogs fed a low-sodium diet as an experimental model of RAAS activation. Renin activity (RA) and angiotensin II levels (AII) were determined using immunoassay-based methods. Benazepril and aldosterone concentration (ALD) were quantified in plasma by mass spectrometry. Population PK/PD models were developed using NONMEM version 7.1.2. A covariate search was performed using the stepwise covariate model building tool of PsN. Standard goodness-of-fit diagnostics, normalised prediction distribution errors, as well as posterior predictive checks and bootstraps were performed to assess the adequacy of selected models.
Results: The pharmacokinetic disposition of benazepril was described using a nonlinear binding model, as described by Toutain et al. (2000) [2]. Cosine functions were identified to fit the periodic nature of RA, AII and ALD well, and served as baseline for the further development of PK/PD models to assess the effects of benazepril on the RAAS. Moving down from the “top” of the renin cascade, benazepril evoked a substantial increase in RA, while decreasing AII and ALD. Bodyweight, gender and sodium intake proved the most significant covariates to explain part of the between-subject variability.
Conclusions: Our data show that benazepril markedly influences RAAS dynamics in dogs. Nonlinear mixed effect modeling helped integrating information on benazepril-induced RAAS inhibition over time and identifying the main determinants of between-animal variability. Differences in biomarkers responses reflect the high level of regulation of the renin-angiotensin cascade.
References:
[1] Atkins C, Bonagura J, Ettinger S, Fox P, Gordon S, Haggstrom J et al. J Vet Intern Med. 2009. 23(6):1142-50.
[2] Toutain PL, Lefebvre HP, King JN. J Pharmacol Exp Ther. 2000. 292(3):1087-93.
Reference: PAGE 21 (2012) Abstr 2352 [www.page-meeting.org/?abstract=2352]
Poster: Endocrine