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Title: Model-based analysis of thromboxane B{sub 2} and prostaglandin E{sub 2} as biomarkers in the safety evaluation of naproxen

Abstract

The assessment of safety in traditional toxicology protocols relies on evidence arising from observed adverse events (AEs) in animals and on establishing their correlation with different measures of drug exposure (e.g., C{sub max} and AUC). Such correlations, however, ignore the role of biomarkers, which can provide further insight into the underlying pharmacological mechanisms. Here we use naproxen as a paradigm drug to explore the feasibility of a biomarker-guided approach for the prediction of AEs in humans. A standard toxicology protocol was set up for the evaluation of effects of naproxen in rat, in which four doses were tested (7.5, 15, 40 and 80 mg/kg). In addition to sparse blood sampling for the assessment of exposure, thromboxane B{sub 2} and prostaglandin E{sub 2} were also collected in satellite groups. Nonlinear mixed effects modelling was used to evaluate the predictive performance of the approach. A one-compartmental model with first order absorption was found to best describe the pharmacokinetics of naproxen. A nonlinear relationship between dose and bioavailability was observed which leads to a less than proportional increase in naproxen concentrations with increasing doses. The pharmacodynamics of TXB{sub 2} and PGE{sub 2} was described by direct inhibition models with maximum pharmacological effects achievedmore » at doses > 7.5 mg/kg. The predicted PKPD relationship in humans was within 10-fold of the values previously published. Moreover, our results indicate that biomarkers can be used to assess interspecies differences in PKPD and extrapolated data from animals to humans. Biomarker sampling should be used systematically in general toxicity studies. - Highlights: • Prediction of a drug's safety profile from preclinical protocols remains challenging. • Pharmacokinetic measures of safe exposure (e.g., AUC) ignore the role of biomarkers. • PKPD relationships enable the evaluation of adverse events in a mechanistic manner. • Major differences exist between rats and humans in the effects of naproxen on TXB{sub 2}. • A biomarker-guided approach may facilitate the prediction of adverse events in humans.« less

Authors:
; ;  [1];  [1]
  1. Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden (Netherlands)
Publication Date:
OSTI Identifier:
22439792
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 278; Journal Issue: 3; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ABSORPTION; BIOLOGICAL AVAILABILITY; BIOLOGICAL MARKERS; BLOOD; CONCENTRATION RATIO; DRUGS; FORECASTING; HUMAN POPULATIONS; PHARMACOLOGY; PROSTAGLANDINS; RATS; SAFETY ANALYSIS; SAMPLING; TOXICITY

Citation Formats

Sahota, Tarjinder, Sanderson, Ian, Danhof, Meindert, Della Pasqua, Oscar, and Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Uxbridge. Model-based analysis of thromboxane B{sub 2} and prostaglandin E{sub 2} as biomarkers in the safety evaluation of naproxen. United States: N. p., 2014. Web. doi:10.1016/J.TAAP.2014.03.010.
Sahota, Tarjinder, Sanderson, Ian, Danhof, Meindert, Della Pasqua, Oscar, & Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Uxbridge. Model-based analysis of thromboxane B{sub 2} and prostaglandin E{sub 2} as biomarkers in the safety evaluation of naproxen. United States. https://doi.org/10.1016/J.TAAP.2014.03.010
Sahota, Tarjinder, Sanderson, Ian, Danhof, Meindert, Della Pasqua, Oscar, and Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Uxbridge. 2014. "Model-based analysis of thromboxane B{sub 2} and prostaglandin E{sub 2} as biomarkers in the safety evaluation of naproxen". United States. https://doi.org/10.1016/J.TAAP.2014.03.010.
@article{osti_22439792,
title = {Model-based analysis of thromboxane B{sub 2} and prostaglandin E{sub 2} as biomarkers in the safety evaluation of naproxen},
author = {Sahota, Tarjinder and Sanderson, Ian and Danhof, Meindert and Della Pasqua, Oscar and Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Uxbridge},
abstractNote = {The assessment of safety in traditional toxicology protocols relies on evidence arising from observed adverse events (AEs) in animals and on establishing their correlation with different measures of drug exposure (e.g., C{sub max} and AUC). Such correlations, however, ignore the role of biomarkers, which can provide further insight into the underlying pharmacological mechanisms. Here we use naproxen as a paradigm drug to explore the feasibility of a biomarker-guided approach for the prediction of AEs in humans. A standard toxicology protocol was set up for the evaluation of effects of naproxen in rat, in which four doses were tested (7.5, 15, 40 and 80 mg/kg). In addition to sparse blood sampling for the assessment of exposure, thromboxane B{sub 2} and prostaglandin E{sub 2} were also collected in satellite groups. Nonlinear mixed effects modelling was used to evaluate the predictive performance of the approach. A one-compartmental model with first order absorption was found to best describe the pharmacokinetics of naproxen. A nonlinear relationship between dose and bioavailability was observed which leads to a less than proportional increase in naproxen concentrations with increasing doses. The pharmacodynamics of TXB{sub 2} and PGE{sub 2} was described by direct inhibition models with maximum pharmacological effects achieved at doses > 7.5 mg/kg. The predicted PKPD relationship in humans was within 10-fold of the values previously published. Moreover, our results indicate that biomarkers can be used to assess interspecies differences in PKPD and extrapolated data from animals to humans. Biomarker sampling should be used systematically in general toxicity studies. - Highlights: • Prediction of a drug's safety profile from preclinical protocols remains challenging. • Pharmacokinetic measures of safe exposure (e.g., AUC) ignore the role of biomarkers. • PKPD relationships enable the evaluation of adverse events in a mechanistic manner. • Major differences exist between rats and humans in the effects of naproxen on TXB{sub 2}. • A biomarker-guided approach may facilitate the prediction of adverse events in humans.},
doi = {10.1016/J.TAAP.2014.03.010},
url = {https://www.osti.gov/biblio/22439792}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 278,
place = {United States},
year = {Fri Aug 01 00:00:00 EDT 2014},
month = {Fri Aug 01 00:00:00 EDT 2014}
}