Pharmacokinetic/Pharmacodynamic Modeling of Renin-Angiotensin Aldosterone Biomarkers Following Angiotensin-Converting Enzyme (ACE) Inhibition Therapy with Benazepril in Dogs

Mochel, Jonathan P.; Fink, Martin; Peyrou, Mathieu; Soubret, Antoine; Giraudel, J. M.; Danhof, Meindert

doi:10.1007/s11095-014-1587-9

Cited by 31 publications

(59 citation statements)

References 52 publications

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“…Based on our findings on the dynamics of the circulating RAAS under physiological (Mochel et al 2013a(Mochel et al , 2014a and RAAS-activated conditions (Mochel et al 2013b(Mochel et al , 2015, various strategies could in theory improve the therapeutic management of cardiovascular diseases in dogs. Essentially, one could think of:…”

Section: Benazepril Markedly Influences the Dynamics Of The Circulatimentioning

confidence: 93%

“…Next to the effect of feeding time on the chronobiology of the RAAS, food composition per se (i.e., dietary sodium) also influences the periodicity of renin. This was shown (i) from the results of the covariate analysis performed under regular diet conditions (0.5% sodium) (Mochel et al 2013a(Mochel et al , 2014a and (ii) from the comparison of the mesor and amplitude estimates of RA in dogs fed a normal (0.5% sodium) vs. a low-sodium (0.05% sodium) regime (Mochel et al 2015). In all studies, decreasing the amount of dietary sodium was found to increase the mesor and amplitude of RA oscillations, suggesting that sodium not only influences the tonic (i.e., mesor), but also the phasic (i.e., amplitude) secretion of renin.…”

Section: Components Of the Renin Cascade Blood Pressure And Urinarymentioning

confidence: 96%

“…In this experiment, the authors reported substantial variations in renin, AI, and AII during placebo treatment, which they described using a periodic function (sum of 2 harmonics) of renin production as the driving force for the episodic profiling of downstream biomarkers AI and AII. In the case of benazepril, the use of a straight line approximation of the mean (instead of a cosine) for modeling of the placebo data would result in overestimating the effect of ACE inhibition on AII and ALD, while underestimating its effect on RA (Mochel et al 2015). Circadian changes in the functioning of the circulating RAAS provide a strong scientific rationale for tailored administration of cardioactive drugs at a time that would optimize efficacy.…”

Section: Modeling and Simulation: A Basis For Optimizing The Dosing Smentioning

confidence: 99%

“…The modulatory action of benazeprilat on the functioning of the circulating RAAS was further characterized using an integrated mechanism-based PKPD modeling approach (Fig. 8) (Mochel et al 2015). The final model, which also described the natural time course of the biomarkers in the absence of the ACE inhibitor (i.e., under placebo treatment), predicted no time delay between the dynamics of benazeprilat, RA, AII, and ALD, which is an indication of a rapid turnover of RAAS biomarkers in plasma.…”

Section: Benazepril Markedly Influences the Dynamics Of The Circulatimentioning

confidence: 99%

“…The modulatory effect of benazeprilat on the RAAS was described using a combination of immediate response models, where benazeprilat concentrations vs. time data served as the driving force for prediction of AII, while RA and ALD levels were derived from the predicted difference in AII during placebo and benazepril treatment. Source: Mochel et al (2015). Reprinted by permission of Springer Similar to humans, peptides of the systemic RAAS and BP oscillate with a clear circadian periodicity in dogs.…”

Section: Benazepril Markedly Influences the Dynamics Of The Circulatimentioning

confidence: 99%

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Chronobiology and Pharmacologic Modulation of the Renin–Angiotensin–Aldosterone System in Dogs: What Have We Learned?

Mochel

Danhof

2015

Reviews of Physiology, Biochemistry and Pharmacology Vol. 169

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Congestive heart failure (CHF) is a primary cause of morbidity and mortality with an increasing prevalence in human and canine populations. Recognition of the role of renin-angiotensin-aldosterone system (RAAS) overactivation in the pathophysiology of CHF has led to significant medical advances. By decreasing systemic vascular resistance and angiotensin II (AII) production, angiotensin-converting enzyme (ACE) inhibitors such as benazepril improve cardiac hemodynamics and reduce mortality in human and dog CHF patients. Although several experiments have pointed out that efficacy of ACE inhibitors depends on the time of administration, little attention is paid to the optimum time of dosing of these medications. A thorough characterization of the chronobiology of the renin cascade has the potential to streamline the therapeutic management of RAAS-related diseases and to help determining the optimal time of drug administration that maximizes efficacy of ACE inhibitors, while minimizing the occurrence of adverse effects. We have developed an integrated pharmacokinetic-pharmacodynamic model that adequately captures the disposition kinetics of the paradigm drug benazeprilat, as well as the time-varying changes of systemic renin-angiotensin-aldosterone biomarkers, without and with ACE inhibition therapy. Based on these chronobiological investigations, the optimal efficacy of ACE inhibitors is expected with bedtime dosing. The data further show that benazepril influences the dynamics of the renin-angiotensin-aldosterone cascade, resulting in a profound decrease in AII and aldosterone (ALD), while increasing renin activity for about 24 h. From the results of recent investigations in human, it is hypothesized that reduction of AII and ALD is one of the drivers of increased survival and improved quality of life in dogs receiving ACE inhibitors. To support and consolidate this hypothesis, additional efforts should be directed toward the collection of circulating RAAS peptides in spontaneous cases of canine CHF. If such a link could be established, profiling of these biomarkers could support determination of the severity of heart failure, complement clinical and echocardiographic findings, and be used for therapeutic drug monitoring purposes.

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Section: Benazepril Markedly Influences the Dynamics Of The Circulatimentioning

confidence: 93%

Section: Components Of the Renin Cascade Blood Pressure And Urinarymentioning

confidence: 96%

Section: Modeling and Simulation: A Basis For Optimizing The Dosing Smentioning

confidence: 99%

Section: Benazepril Markedly Influences the Dynamics Of The Circulatimentioning

confidence: 99%

Section: Benazepril Markedly Influences the Dynamics Of The Circulatimentioning

confidence: 99%

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Chronobiology and Pharmacologic Modulation of the Renin–Angiotensin–Aldosterone System in Dogs: What Have We Learned?

Mochel

Danhof

2015

Reviews of Physiology, Biochemistry and Pharmacology Vol. 169

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Modeling of Large Pharmacokinetic Data Using Nonlinear Mixed‐Effects: A Paradigm Shift in Veterinary Pharmacology. A Case Study With Robenacoxib in Cats

Pelligand

Soubret

Jn³

et al. 2016

CPT Pharmacom & Syst Pharma

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The objective of this study was to model the pharmacokinetics (PKs) of robenacoxib in cats using a nonlinear mixed‐effects (NLME) approach, leveraging all available information collected from cats receiving robenacoxib s.c. and/or i.v.: 47 densely sampled laboratory cats and 36 clinical cats sparsely sampled preoperatively. Data from both routes were modeled sequentially using Monolix 4.3.2. Influence of parameter correlations and available covariates (age, gender, bodyweight, and anesthesia) on population parameter estimates were evaluated by using multiple samples from the posterior distribution of the random effects. A bicompartmental disposition model with simultaneous zero and first‐order absorption best described robenacoxib PKs in blood. Clearance was 0.502 L/kg/h and the bioavailability was high (78%). The absorption constant point estimate (Ka = 0.68 h−1) was lower than beta (median, 1.08 h−1), unveiling flip‐flop kinetics. No dosing adjustment based on available covariates information is advocated. This modeling work constitutes the first application of NLME in a large feline population.

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Model‐Based Reverse Translation Between Veterinary and Human Medicine: The One Health Initiative

Schneider

Balbas-Martinez

Jergens

et al. 2017

CPT Pharmacom & Syst Pharma

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There is growing concern about the limitations of rodent models with regard to recapitulation of human disease pathogenesis. Computational modeling of data from humans and animals sharing similar diseases provides an opportunity for parallel drug development in human and veterinary medicine. This “reverse translational” approach needs to be supported by continuing efforts to refine the in silico tools that allow extrapolation of results between species.

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Pharmacokinetic/Pharmacodynamic Modeling of Renin-Angiotensin Aldosterone Biomarkers Following Angiotensin-Converting Enzyme (ACE) Inhibition Therapy with Benazepril in Dogs

Abstract: The model provides a quantitative framework for better understanding the effect of ACE inhibition on the dynamics of the systemic RAAS in dogs.

Cited by 31 publications

References 52 publications

Chronobiology and Pharmacologic Modulation of the Renin–Angiotensin–Aldosterone System in Dogs: What Have We Learned?

Chronobiology and Pharmacologic Modulation of the Renin–Angiotensin–Aldosterone System in Dogs: What Have We Learned?

Modeling of Large Pharmacokinetic Data Using Nonlinear Mixed‐Effects: A Paradigm Shift in Veterinary Pharmacology. A Case Study With Robenacoxib in Cats

Model‐Based Reverse Translation Between Veterinary and Human Medicine: The One Health Initiative

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