PMID- 24667227
OWN - NLM
STAT- MEDLINE
DCOM- 20140902
LR  - 20151119
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Linking)
VI  - 278
IP  - 3
DP  - 2014 Aug 1
TI  - Model-based analysis of thromboxane B(2) and prostaglandin E(2) as biomarkers in the 
      safety evaluation of naproxen.
PG  - 209-19
LID - S0041-008X(14)00096-9 [pii]
LID - 10.1016/j.taap.2014.03.010 [doi]
AB  - 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 B(2) and prostaglandin E(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(2) and PGE(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.
CI  - Copyright (c) 2014 Elsevier Inc. All rights reserved.
FAU - Sahota, Tarjinder
AU  - Sahota T
AD  - Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The 
      Netherlands.
FAU - Sanderson, Ian
AU  - Sanderson I
AD  - Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The 
      Netherlands.
FAU - Danhof, Meindert
AU  - Danhof M
AD  - Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The 
      Netherlands.
FAU - Della Pasqua, Oscar
AU  - Della Pasqua O
AD  - Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The 
      Netherlands; Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, 
      Uxbridge, UK.
LA  - eng
PT  - Comparative Study
PT  - Journal Article
DEP - 20140322
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (Biomarkers)
RN  - 0 (Cyclooxygenase Inhibitors)
RN  - 54397-85-2 (Thromboxane B2)
RN  - 57Y76R9ATQ (Naproxen)
RN  - K7Q1JQR04M (Dinoprostone)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents, Non-Steroidal/administration & dosage/*adverse 
      effects/blood/pharmacokinetics
MH  - Biological Availability
MH  - Biomarkers/blood
MH  - Computer Simulation
MH  - Cyclooxygenase Inhibitors/administration & dosage/*adverse 
      effects/blood/pharmacokinetics
MH  - Dinoprostone/*blood
MH  - Dose-Response Relationship, Drug
MH  - Feasibility Studies
MH  - Humans
MH  - Intestinal Absorption
MH  - Male
MH  - Metabolic Clearance Rate
MH  - *Models, Biological
MH  - Naproxen/administration & dosage/*adverse effects/blood/pharmacokinetics
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Risk Assessment/methods
MH  - Species Specificity
MH  - Thromboxane B2/*blood
OTO - NOTNLM
OT  - Biomarkers
OT  - Drug development
OT  - Long term safety
OT  - Naproxen
OT  - PKPD modelling
OT  - Safety pharmacology
EDAT- 2014/03/29 06:00
MHDA- 2014/09/03 06:00
CRDT- 2014/03/27 06:00
PHST- 2013/12/13 00:00 [received]
PHST- 2014/02/25 00:00 [revised]
PHST- 2014/03/13 00:00 [accepted]
PHST- 2014/03/27 06:00 [entrez]
PHST- 2014/03/29 06:00 [pubmed]
PHST- 2014/09/03 06:00 [medline]
AID - S0041-008X(14)00096-9 [pii]
AID - 10.1016/j.taap.2014.03.010 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2014 Aug 1;278(3):209-19. doi: 
      10.1016/j.taap.2014.03.010. Epub 2014 Mar 22.