PMID- 25884765
OWN - NLM
STAT- MEDLINE
DCOM- 20160531
LR  - 20240323
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 172
IP  - 15
DP  - 2015 Aug
TI  - Model-based prediction of the acute and long-term safety profile of naproxen in 
      rats.
PG  - 3861-74
LID - 10.1111/bph.13167 [doi]
AB  - BACKGROUND AND PURPOSE: Despite the increasing importance of biomarkers as 
      predictors of drug effects, toxicology protocols continue to rely on the 
      experimental evidence of adverse events (AEs) as a basis for establishing the 
      link between indicators of safety and drug exposure. Furthermore, biomarkers may 
      facilitate the translation of findings from animals to humans. Combined with a 
      model-based approach, biomarker data have the potential to predict long-term 
      effects arising from prolonged drug exposure. Here, we used naproxen as a 
      paradigm to explore the feasibility of a biomarker-guided approach for the 
      prediction of long-term AEs in humans. EXPERIMENTAL APPROACH: An experimental 
      toxicology protocol was set up for evaluating the effects of naproxen in rats, in 
      which four active doses were tested (7.5, 15, 40 and 80 mg.kg(-1) ). In addition 
      to AE monitoring and histology, a few blood samples were also collected for the 
      assessment of drug exposure, TXB2 and PGE2 levels. Non-linear mixed effects 
      modelling was used to analyse the data and identify covariate factors on the 
      incidence and severity of AEs. KEY RESULTS: Modelling results showed that besides 
      drug exposure, maximum PGE2 inhibition and treatment duration were also 
      predictors of gastrointestinal ulceration. Although PGE2 levels were clearly 
      linked to the incidence rates, it appeared that ulceration severity is better 
      predicted by measures of drug exposure. CONCLUSIONS AND IMPLICATIONS: These 
      results show that the use of a model-based approach provides the opportunity to 
      integrate pharmacokinetics, pharmacodynamics and toxicity data, enabling 
      optimization of the design, analysis and interpretation of toxicology 
      experiments.
CI  - (c) 2015 The British Pharmacological Society.
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.
AD  - Clinical Pharmacology, Modelling and Simulation, GlaxoSmithKline, Uxbridge, UK.
AD  - Clinical Pharmacology & Therapeutics, University College London, London, UK.
LA  - eng
PT  - Journal Article
DEP - 20150629
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (Biomarkers)
RN  - 54397-85-2 (Thromboxane B2)
RN  - 57Y76R9ATQ (Naproxen)
RN  - K7Q1JQR04M (Dinoprostone)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents, Non-Steroidal/*adverse effects/pharmacokinetics
MH  - Biomarkers/blood
MH  - Dinoprostone/blood
MH  - Dose-Response Relationship, Drug
MH  - Male
MH  - *Models, Biological
MH  - Naproxen/*adverse effects/pharmacokinetics
MH  - Peptic Ulcer/blood/chemically induced
MH  - Rats
MH  - Thromboxane B2/blood
PMC - PMC4523341
EDAT- 2015/04/18 06:00
MHDA- 2016/06/01 06:00
PMCR- 2016/08/01
CRDT- 2015/04/18 06:00
PHST- 2014/08/24 00:00 [received]
PHST- 2015/02/08 00:00 [revised]
PHST- 2015/04/15 00:00 [accepted]
PHST- 2015/04/18 06:00 [entrez]
PHST- 2015/04/18 06:00 [pubmed]
PHST- 2016/06/01 06:00 [medline]
PHST- 2016/08/01 00:00 [pmc-release]
AID - 10.1111/bph.13167 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2015 Aug;172(15):3861-74. doi: 10.1111/bph.13167. Epub 2015 Jun 
      29.