Correlation between in vitro and in vivo concentration–effect relationships of naproxen in rats and healthy volunteers

Abstract

1 Understanding the mechanisms underlying the analgesic effect of new cyclooxygenase inhibitors is essential to identify dosing requirements in early stages of drug development. Accurate extrapolation to humans of in vitro and in vivo findings in preclinical species is needed to optimise dosing regimen in inflammatory conditions. 2 The current investigation characterises the inhibition of prostaglandin E2 (PGE 2 ) and thromboxane B2 (TXB 2 ) by naproxen in vitro and in vivo in rat and human blood. The inhibition of PGE 2 in the absence or presence of increasing concentrations of naproxen (10 À8 -10 À1 M) was measured by ex vivo whole blood stimulation with LPS, whereas inhibition of TXB 2 was measured in serum following blood clotting. In further experiments, inhibition of PGE 2 and TXB 2 levels was also assessed ex vivo in animals treated with naproxen (2.5, 10, 25 mg kg À1 ). Subsequently, pharmacokinetic (PK)/pharmacodynamics (PD) modelling of in vitro and in vivo data was performed using nonlinear mixed effects in NONMEM (V). 3 Inhibition of PGE 2 and TXB 2 was characterised by a sigmoid E max model. The exposure-response relationships in vitro and in vivo were of the same order of magnitude in both species. IC 80 estimates obtained in vitro were similar for PGE 2 inhibition (130.8711 and 131.9719 10 À6 M, mean7s.d. for humans and rats, respectively), but slightly different for TXB 2 inhibition (103.9715 and 151.4740 10 À6 M, mean7s.d. for humans and rats, respectively, Po 0.05). These differences, however, may not be biologically relevant. 4 The results confirm the value of exposure-effect relationships determined in vitro as a means to predict the pharmacological activity in vivo. This analysis also highlights the need to parameterise concentration-effect relationships in early drug development, as indicated by the estimates of IC 80 for PGE 2 and TXB 2 inhibition.

Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats

“…No delay in the onset of inhibition was observed, revealing that the effect compartment was located in the central compartment. This result agrees with a previous report that described the use of naproxen [14,23] .…”

“…This indicates that PGE 2 can be used as a specific biomarker to explain and understand the variability in the therapeutic of these drugs [12] . Recently, efforts have been made to establish the relationship between biomarkers, pain measurement and safety [13][14][15][16] . However, information on the integrated pharmacokinetic-pharmacodynamic profiles of these drugs under normal and chronic inflammatory conditions is still limited.…”

In Vitro–In Vivo Correlation for Low-Clearance Compounds Using Hepatocyte Relay Method

“…Fold Difference In Vivo/Relay Method ml/min/kg ml/min/kg Ranitidine 4.4 (Hallifax et al, 2010) 3.1 6 0.48 1.4 Tolbutamide 4.9 (Brown et al, 2007) 7.4 6 0.40 (Di et al, 2012) 0.66 Antipyrine 0.6 (Hallifax et al, 2010) 1.3 6 0.25 0.46 Naproxen 25 (Huntjens et al, 2006;Hallifax et al, 2010) 18 6 3. dmd.aspetjournals.org the in vivo and in vitro intrinsic clearance ratios were within 2-fold, suggesting good IVIVC. The exceptions involved significant active uptake from transporters or contribution of extrahepatic metabolism.…”

Use of Sensory Methods for Detecting Target Engagement in Clinical Trials of New Analgesics

“…This is often done ex vivo, as when the blood of a drug-exposed human subject is treated with challenge agents to evoke a pharmacological response (e.g., release of prostanoids in whole blood as a measure of cyclooxygenase activity 4 ). Although seemingly simple and sufficiently robust (and potentially translatable between species), such markers do not test the target engagement of novel analgesics in the relevant tissue or pathway, and have not yet been validated.…”