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

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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.

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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

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Acknowledgements

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

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Authors and Affiliations

  1. Novartis Pharma AG, Modeling & Simulation Pharmacology, Postfach CH-4002, Basel, Switzerland

    Hanna E. Silber

  2. Novartis Centre de Recherche Santé Animale SA, CH-1566, Saint-Aubin, Switzerland

    Claudia Burgener, Mathieu Peyrou, Martin Jung & Jerome M. Giraudel

  3. Novartis Santé Animale SAS, FR-92500, Rueil-Malmaison, France

    Ingrid M. Letellier & Philippe Gruet

  4. Novartis Animal Health Inc., CH-4058, Basel, Switzerland

    Jonathan N. King

Authors
  1. Hanna E. Silber
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  2. Claudia Burgener
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  3. Ingrid M. Letellier
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  4. Mathieu Peyrou
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  5. Martin Jung
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  6. Jonathan N. King
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  7. Philippe Gruet
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  8. Jerome M. Giraudel
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Correspondence to Jerome M. Giraudel.

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Silber, H.E., Burgener, C., Letellier, I.M. et al. Population Pharmacokinetic Analysis of Blood and Joint Synovial Fluid Concentrations of Robenacoxib from Healthy Dogs and Dogs with Osteoarthritis. Pharm Res 27, 2633–2645 (2010). https://doi.org/10.1007/s11095-010-0262-z

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  • DOI: https://doi.org/10.1007/s11095-010-0262-z

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