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Pharmacokinetic-Pharmacodynamic Modeling of the Inhibitory Effects of Naproxen on the Time-Courses of Inflammatory Pain, Fever, and the Ex Vivo Synthesis of TXB2 and PGE2 in Rats

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ABSTRACT

Purpose

To quantify and compare the time-course and potency of the analgesic and antipyretic effects of naproxen in conjunction with the inhibition of PGE2 and TXB2.

Methods

Analgesia was investigated in a rat model with carrageenan-induced arthritis using a gait analysis method. Antipyretics were studied in a yeast-induced fever model using telemetrically recorded body temperature. Inhibition of TXB2 and PGE2 synthesis was determined ex vivo. Pharmacokinetic profiles were obtained in satellite animals. Population PKPD modeling was used to analyze the data.

Results

The IC50 values (95% CI) of naproxen for analgesia (27 (0–130) μM), antipyretics (40 (30–65) μM) and inhibition of PGE2 (13 (6–45) μM) were in similar range, whereas inhibition of TXB2 (5 (4–8) μM) was observed at lower concentrations. Variability in the behavioral measurement of analgesia was larger than for the other endpoints. The inhibition of fever by naproxen was followed by an increased rebound body temperature.

Conclusion

Due to better sensitivity and similar drug-induced inhibition, the biomarker PGE2 and the antipyretic effect would be suitable alternative endpoints to the analgesic effects for characterization and comparisons of potency and time-courses of drug candidates affecting the COX-2 pathway and to support human dose projections.

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Abbreviations

COX:

cyclooxygenase

CV%:

coefficient of variation

LPS:

lipopolysaccharide

NSAIDs:

nonsteroidal anti-inflammatory drugs

PGE2 :

prostaglandin E2

TXB2 :

thromboxane B2

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ACKNOWLEDGMENTS

The authors thank Lars I. Andersson for help with TXB2 & PGE2 assays, Ulrika Määttä for assisting with biomarker sampling and Kristina Brunfelter, Sveinn Briem, Yvonne Jaksch, and Jonas Malmberg for help with the various bioanalyses.

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Author notes

  1. Elke H. J. Krekels

    Present address: Division of Pharmacology Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands

Authors and Affiliations

  1. DMPK, CNSP iMed Science Södertälje, AstraZeneca Research and Development, Innovative Medicines, SE-151 85, Södertälje, Sweden

    Elke H. J. Krekels, Marie Angesjö, Ingemo Sjögren & Sandra A. G. Visser

  2. Neuroscience, CNSP iMed Science Södertälje, AstraZeneca Research and Development, Innovative Medicines, SE-151 85, Södertälje, Sweden

    Kristina Ängeby Möller & Odd-Geir Berge

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  1. Elke H. J. Krekels
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Correspondence to Sandra A. G. Visser.

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Krekels, E.H.J., Angesjö, M., Sjögren, I. et al. Pharmacokinetic-Pharmacodynamic Modeling of the Inhibitory Effects of Naproxen on the Time-Courses of Inflammatory Pain, Fever, and the Ex Vivo Synthesis of TXB2 and PGE2 in Rats. Pharm Res 28, 1561–1576 (2011). https://doi.org/10.1007/s11095-011-0389-6

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  • DOI: https://doi.org/10.1007/s11095-011-0389-6

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