title: Model-based analysis of thromboxane B₂ and prostaglandin E₂ 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., 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.
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands.
authors.forename: Tarjinder
authors.initials: T
authors.lastname: Sahota
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands.
authors.forename: Ian
authors.initials: I
authors.lastname: Sanderson
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands.
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands; Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Uxbridge, UK.
authors.forename: Oscar
authors.initials: O
authors.lastname: Della Pasqua
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D001682:Biological Availability; D015415:Biomarkers / Q000097:blood; D003198:Computer Simulation; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D015232:Dinoprostone / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009288:Naproxen / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment / Q000379:methods; D013045:Species Specificity; D013929:Thromboxane B2 / Q000097:blood*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D016861:Cyclooxygenase Inhibitors; D013929:Thromboxane B2; D009288:Naproxen; D015232:Dinoprostone
keywords: Biomarkers; Drug development; Long term safety; Naproxen; PKPD modelling; Safety pharmacology