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Pharmaceutical Research

, Volume 27, Issue 12, pp 2633–2645 | Cite as

Population Pharmacokinetic Analysis of Blood and Joint Synovial Fluid Concentrations of Robenacoxib from Healthy Dogs and Dogs with Osteoarthritis

  • Hanna E. Silber
  • Claudia Burgener
  • Ingrid M. Letellier
  • Mathieu Peyrou
  • Martin Jung
  • Jonathan N. King
  • Philippe Gruet
  • Jerome M. GiraudelEmail author
Research Paper

ABSTRACT

Purpose

The purpose of this population analysis was to characterize the pharmacokinetic properties of robenacoxib in blood and stifle joint synovial fluid of dogs.

Methods

Data were obtained from two studies: 1) 8 healthy Beagle dogs in which an acute inflammation was induced by injection of urate crystals into one joint; 2) 95 dogs from various breeds diagnosed with osteoarthritis (OA). Robenacoxib concentrations in blood and synovial fluid were measured using a validated HPLC-UV and LC-MS method. Non-linear mixed effects modeling was performed using NONMEM6.

Results

A two-compartment pharmacokinetic model with linear elimination was developed to describe blood concentrations of robenacoxib. Blood clearance in healthy animals was found to be 75% higher than in OA dogs. Synovial fluid concentrations were modeled using an effect-compartment-type model predicting longer residence times in OA dogs compared to healthy Beagles (e.g. concentrations above the IC50 for COX-2, respectively, 16 h vs. 10 h at 1.5 mg/kg).

Conclusions

Robenacoxib was found to reside longer at the effect site (inflamed joint) compared to blood in both healthy and OA dogs. These results may explain the good efficacy observed with once-daily dosing in clinical trials and the high safety index of robenacoxib in dogs.

KEY WORDS

COXIB dog robenacoxib tissue selectivity 

ABBREVIATIONS

BLQ

below limit of quantification

COX

Cyclooxygenase

COX-1

Cyclooxygenase-1

COX-2

Cyclooxygenase-2

FOCE

first-order conditional estimation method

HPLC-UV

high pressure liquid chromatography with ultraviolet detection

IIV

inter-individual variability

IOV

inter-occasion variability

LC-MS

liquid chromatography with mass spectrometry

LLOQ

lower limit of quantification

MTT

Mean Transit Time

N

number of transit compartments

NSAID

non-steroidal anti-inflammatory drug

OA

osteoarthritis

OFV

objective function value

VICH

international cooperation on harmonisation of technical requirements for registration of veterinary medicinal products

VPC

visual predictive check

Notes

Acknowledgements

This work was sponsored by Novartis Animal Health Inc., CH-4058 Basel, Switzerland.

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Hanna E. Silber
    • 1
  • Claudia Burgener
    • 2
  • Ingrid M. Letellier
    • 3
  • Mathieu Peyrou
    • 2
  • Martin Jung
    • 2
  • Jonathan N. King
    • 4
  • Philippe Gruet
    • 3
  • Jerome M. Giraudel
    • 2
    Email author
  1. 1.Novartis Pharma AG, Modeling & Simulation PharmacologyBaselSwitzerland
  2. 2.Novartis Centre de Recherche Santé Animale SASaint-AubinSwitzerland
  3. 3.Novartis Santé Animale SASRueil-MalmaisonFrance
  4. 4.Novartis Animal Health Inc.BaselSwitzerland

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