caa a22 4500 445312211 CHVBK 20180317142634.0 cr unu---uuuuu 170323e20110701xx s 000 0 eng 10.1007/s11095-011-0389-6 doi (NATIONALLICENCE)springer-10.1007/s11095-011-0389-6 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 [Elektronische Daten] [Elke Krekels, Marie Angesjö, Ingemo Sjögren, Kristina Ängeby Möller, Odd-Geir Berge, Sandra Visser] 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. Springer Science+Business Media, LLC, 2011 analgesia nationallicence fever nationallicence naproxen nationallicence pharmacokinetic-pharmacodynamic modeling nationallicence prostaglandins nationallicence COX : cyclooxygenase nationallicence CV% : coefficient of variation nationallicence LPS : lipopolysaccharide nationallicence NSAIDs : nonsteroidal anti-inflammatory drugs nationallicence PGE2 : prostaglandin E2 nationallicence TXB2 : thromboxane B2 nationallicence Krekels Elke DMPK, CNSP iMed Science Södertälje, AstraZeneca Research and Development, Innovative Medicines, SE-151 85, Södertälje, Sweden aut Angesjö Marie DMPK, CNSP iMed Science Södertälje, AstraZeneca Research and Development, Innovative Medicines, SE-151 85, Södertälje, Sweden aut Sjögren Ingemo DMPK, CNSP iMed Science Södertälje, AstraZeneca Research and Development, Innovative Medicines, SE-151 85, Södertälje, Sweden aut Ängeby Möller Kristina Neuroscience, CNSP iMed Science Södertälje, AstraZeneca Research and Development, Innovative Medicines, SE-151 85, Södertälje, Sweden aut Berge Odd-Geir Neuroscience, CNSP iMed Science Södertälje, AstraZeneca Research and Development, Innovative Medicines, SE-151 85, Södertälje, Sweden aut Visser Sandra DMPK, CNSP iMed Science Södertälje, AstraZeneca Research and Development, Innovative Medicines, SE-151 85, Södertälje, Sweden aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/7(2011-07-01), 1561-1576 0724-8741 28:7<1561 2011 28 11095 https://doi.org/10.1007/s11095-011-0389-6 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0389-6 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Krekels Elke DMPK, CNSP iMed Science Södertälje, AstraZeneca Research and Development, Innovative Medicines, SE-151 85, Södertälje, Sweden aut NATIONALLICENCE 700 1- Angesjö Marie DMPK, CNSP iMed Science Södertälje, AstraZeneca Research and Development, Innovative Medicines, SE-151 85, Södertälje, Sweden aut NATIONALLICENCE 700 1- Sjögren Ingemo DMPK, CNSP iMed Science Södertälje, AstraZeneca Research and Development, Innovative Medicines, SE-151 85, Södertälje, Sweden aut NATIONALLICENCE 700 1- Ängeby Möller Kristina Neuroscience, CNSP iMed Science Södertälje, AstraZeneca Research and Development, Innovative Medicines, SE-151 85, Södertälje, Sweden aut NATIONALLICENCE 700 1- Berge Odd-Geir Neuroscience, CNSP iMed Science Södertälje, AstraZeneca Research and Development, Innovative Medicines, SE-151 85, Södertälje, Sweden aut NATIONALLICENCE 700 1- Visser Sandra DMPK, CNSP iMed Science Södertälje, AstraZeneca Research and Development, Innovative Medicines, SE-151 85, Södertälje, Sweden aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/7(2011-07-01), 1561-1576 0724-8741 28:7<1561 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer