Model-based analysis of thromboxane B2 and prostaglandin E2 as biomarkers in the safety evaluation of naproxen.
Toxicol Appl Pharmacol
; 278(3): 209-19, 2014 Aug 01.
Article
en En
| MEDLINE
| ID: mdl-24667227
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., Cmax 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 B2 and prostaglandin E2 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 TXB2 and PGE2 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tromboxano B2
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Dinoprostona
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Antiinflamatorios no Esteroideos
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Naproxeno
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Inhibidores de la Ciclooxigenasa
/
Modelos Biológicos
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Límite:
Animals
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Humans
/
Male
Idioma:
En
Revista:
Toxicol Appl Pharmacol
Año:
2014
Tipo del documento:
Article
País de afiliación:
Países Bajos
Pais de publicación:
Estados Unidos