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

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Abstract

Purpose

The objective of this research was to provide a comprehensive description of the effect of benazepril on the dynamics of the renin-angiotensin aldosterone system (RAAS) in dogs.

Methods

Blood specimens for renin activity (RA), angiotensin II (AII), and aldosterone (ALD) quantitation in plasma were drawn from 12 healthy adult beagle dogs randomly allocated to 2 treatment groups: (i) benazepril 5 mg PO, q24 h (n: 6) and (ii) placebo (n: 6), in a cross-over design. A mechanism-based pharmacokinetic/pharmacodynamic model, which includes the periodic nature of RA, AII, and ALD during placebo treatment and the subsequent changes in dynamics following repeated dosing with benazepril, was developed.

Results

The disposition kinetics of benazepril active metabolite, benazeprilat, was characterized using a saturable binding model to the angiotensin converting enzyme. The modulatory effect of benazeprilat on the RAAS was described using a combination of immediate response models. Our data show that benazepril noticeably influences the dynamics of the renin cascade, resulting in a substantial decrease in AII and ALD, while increasing RA throughout the observation span.

Conclusions

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

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Abbreviations

ACE:

Angiotensin-converting enzyme

AII:

Angiotensin II

ALD:

Aldosterone

ARA:

Aldosterone receptor antagonist

ARB:

Angiotensin II receptor blocker

BSV:

Between-subject variability (standard deviation of the random effect)

CHF:

Congestive heart failure

CV%:

Coefficient of variation (%)

CVHD:

Chronic valvular heart disease

EIA:

Enzyme immunoassay

MB:

Mechanism-based

OFV:

Objective function value

PD:

Pharmacodynamic

PK:

Pharmacokinetics

PO:

Per os

RA:

Renin activity

RAAS:

Renin-angiotensin-aldosterone system

RSE:

Relative standard error (equivalent to CV%)

SD:

Standard deviation

TMDD:

Target-mediated drug disposition

WRES:

Weighted residuals

C ij :

ng/ml, or nmol/l (nM) Predicted total benazeprilat concentration at time t ij for an individual i

Δ ij :

pg/ml Predicted difference between AII concentrations during placebo treatment and those at corresponding times t ij after benazepril administration for an individual i

T inf :

h Duration of the hypothetical infusion of benazepril into the depot compartment

ka :

h−1 First-order rate constant representing the absorption of benazepril into the central compartment and its in vivo conversion to benazeprilat

k 10 :

h−1 First-order rate constant of benazeprilat elimination from the central compartment

k 1 :

nM−1.h−1 Second-order rate constant of association of the benazeprilat-ACE complex

k 2 :

h−1 First-order rate constant of dissociation of the benazeprilat-ACE complex

BS :

nM Maximal binding capacity to circulating ACE

V c /F :

l/kg Apparent volume of distribution of benazeprilat

Cl/F :

l.h−1/kg Apparent systemic clearance of benazeprilat

E :

− Global extraction coefficient of benazeprilat

M :

pg/ml or pg/ml.h−1 Mesor (daily average of rhythm)

A :

pg/ml or pg/ml.h−1 Amplitude of the cosine function

ψ :

h Acrophase (or time of peak) of the cosine function

τ :

h Period of the cosine function

I max (AII) :

− Maximum inhibition of AII production

IC 50 (AII) :

ng/ml Benazeprilat concentration that produces half of the maximum inhibition of AII

γ (AII) :

− Hill coefficient of the AII vs. benazeprilat effect curve

E max (RA) :

− Maximum stimulatory effect on RA

EC 50 (RA) :

pg/ml Difference in AII between placebo and benazepril-treated dogs for achieving 50% of the maximal stimulation of RA

γ (RA) :

− Hill coefficient of the RA vs. AII effect curve

I max (AL D) :

− Maximum inhibition of ALD production

IC 50 (ALD) :

pg/ml Difference in AII between placebo and benazepril-treated dogs for achieving 50% of the maximal inhibition of ALD

γ (ALD) :

− Hill coefficient of the ALD vs. AII effect curve

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ACKNOWLEDGMENTS AND DISCLOSURES

These investigations were conducted at the Centre de Recherche Sante Animale SA (CRA) of Novartis Animal Health, located in St-Aubin, Switzerland.

With the exception of Prof. Meindert Danhof, the authors of the manuscript are Novartis employees. The experiments were supported by Novartis Animal Health, Basel, Switzerland.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Leiden-Academic Centre for Drug Research, 2300, Leiden, The Netherlands

    Jonathan P. Mochel & Meindert Danhof

  2. Department of Integrated Quantitative Sciences, Novartis Campus St. Johann, WSJ-27.6.023, 4002, Basel, Switzerland

    Jonathan P. Mochel, Martin Fink & Antoine Soubret

  3. Department of Therapeutics Research, Novartis Centre de Recherche Sante Animale SA, 1566, St-Aubin, Switzerland

    Mathieu Peyrou

  4. Department of Research and Development, Novartis Werk Rosental, 4058, Basel, Switzerland

    Jérôme M. Giraudel

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  1. Jonathan P. Mochel
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Corresponding author

Correspondence to Jonathan P. Mochel.

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ESM 3

Mirror plots of the full pharmacokinetic/pharmacodynamic model. (A) Benazeprilat, (B) Angiotensin II, (C) Renin activity, (D) Aldosterone. Comparison of predictions (individual, population) obtained from the raw observations and the simulated datasets using Xpose version 4.1. LNDV.1: observations (log scale) from the original or the simulated datafile. The mirror plots option of Perl-speaks-NONMEM was used to produce 3 simulation table files. Using the same model structure, these simulated datasets were then used as input files to derive a new set of parameter estimates. The dispersion pattern obtained from the 3 simulated datasets ‘mirrored’ the diagnostic plots obtained with the original data, which indicates that the model structure is well-characterized. (GIF 139 kb)

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Mochel, J.P., Fink, M., Peyrou, M. et al. Pharmacokinetic/Pharmacodynamic Modeling of Renin-Angiotensin Aldosterone Biomarkers Following Angiotensin-Converting Enzyme (ACE) Inhibition Therapy with Benazepril in Dogs. Pharm Res 32, 1931–1946 (2015). https://doi.org/10.1007/s11095-014-1587-9

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