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
REFERENCES
Flower RJ. The development of COX-2 inhibitors. Nat Rev Drug Discov. 2003;2(3):179–91.
Lees P, Giraudel J, Landoni MF, Toutain PL. PK-PD integration and PK-PD modelling of nonsteroidal anti-inflammatory drugs: principles and applications in veterinary pharmacology. J Vet Pharmacol Ther. 2004;27(6):491–502.
Giraudel JM, Toutain PL, King JN, Lees P. Differential inhibition of cyclooxygenase isoenzymes in the cat by the COX-2 selective drug robenacoxib. J Vet Pharmacol Ther. 2009;32(1):31–40.
King JN, Dawson J, Esser RE, Fujimoto R, Kimble EF, Maniara W, et al. Pre-clinical pharmacology of robenacoxib: a novel selective inhibitor of cyclooxygenase-2. J Vet Pharmacol Ther. 2009;32(1):1–17.
King JN, Rudaz C, Borer L, Jung M, Seewald W, Lees P. In vitro and ex vivo inhibition of canine cyclooxygenase isoforms by robenacoxib: a comparative study. Res Vet Sci. 2010;88(3):497–506.
Jung M, Lees P, Seewald W, King JN. Analytical determination and pharmacokinetics of robenacoxib in the dog. J Vet Pharmacol Ther. 2009;32(1):41–8.
Gruet P, Seewald W, King JN. Subcutaneous and oral robenacoxib versus meloxicam for the treatment of acute pain and inflammation associated with orthopedic surgery in dogs; a randomized, non-inferiority field study. Am J Vet Res. 2010; accepted for publication.
Reymond N, Speranza C, Gruet P, Seewald W, King JN. Robenacoxib versus carprofen for the treatment of canine osteoarthritis; a randomized, non-inferiority field study. J Vet Pharmacol Therap. 2010; submitted for publication.
King JN, Arnaud JP, Goldenthal EI, Gruet P, Jung M, Seewald W, Lees P. Robenacoxib in the dog: target species safety in relation to extent and duration of inhibition of COX-1 and COX-2. J Vet Pharmacol Therap. 2010; doi:10.1111/j.1365-2885.2010.01209.x.
Esser R, Berry C, Du Z, Dawson J, Fox A, Fujimoto RA, et al. Preclinical pharmacology of lumiracoxib: a novel selective inhibitor of cyclooxygenase-2. Br J Pharmacol. 2005;144(4):538–50.
Scott G, Rordorf C, Reynolds C, Kalbag J, Looby M, Milosavljev S, et al. Pharmacokinetics of lumiracoxib in plasma and synovial fluid. Clin Pharmacokinet. 2004;43(7):467–78.
Brune K, Furst DE. Combining enzyme specificity and tissue selectivity of cyclooxygenase inhibitors: towards better tolerability? Rheumatology. 2007;46(6):911–9.
Schmid VB, Spreng DE, Seewald W, Jung M, Lees P, King JN. Analgesic and anti-inflammatory actions of robenacoxib in acute joint inflammation in the dog. J Vet Pharmacol Ther. 2010;33(2):118–31.
Savic RM, Jonker DM, Kerbusch T, Karlsson MO. Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokinet Parmacodyn. 2007;34(5):711–26.
Sheiner LB, Stanski DR, Vozeh S, Miller RD, Ham J. Simultaneous modeling of pharmacokinetics and pharmacodynamics: application to d-tubocurarine. Clin Pharmacol Ther. 1979;25(3):358–71.
Karlsson MO, Sheiner LB. The importance of modeling interoccasion variability in population pharmacokinetic analyses. J Pharmacokinet Biopharm. 1993;21(6):735–50.
Silber HE, Kjellsson MC, Karlsson MO. The impact of misspecification of residual error or correlation structure on the type I error rate for covariate inclusion. J Pharmacokinet Pharmacodyn. 2009;36(1):81–99.
Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Biopharm. 2001;28(5):481–504.
Jonsson EN, Karlsson MO. Xpose—an S-plus based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed. 1999;58(1):51–64.
Savic RM, Karlsson MO. Importance of shrinkage in empirical bayes estimates for diagnostics: problems and solutions. AAPS J. 2009;11(3):558–69.
Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. J Proc Nat Acad Sci USA. 1999;96(17):7563–8.
Renton KW. Alteration of drug biotransformation and elimination during infection and inflammation. Pharmacol Ther. 2001;92(2–3):147–63.
Renton KW. Regulation of drug metabolism and disposition during inflammation and infection. Expert Opin Drug Metab Toxicol. 2005;1(4):629–40.
Qian M, West W, Wu JT, Lu B, Christ DD. Development of a dog microdialysis model for determining synovial fluid pharmacokinetics of anti-arthritis compounds exemplified by methotrexate. Pharm Res. 2003;20(4):605–10.
Acknowledgements
This work was sponsored by Novartis Animal Health Inc., CH-4058 Basel, Switzerland.
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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