PMID- 16369700
OWN - NLM
STAT- MEDLINE
DCOM- 20060619
LR  - 20181113
IS  - 1567-567X (Print)
IS  - 1567-567X (Linking)
VI  - 33
IP  - 1
DP  - 2006 Feb
TI  - Reducing whole body physiologically based pharmacokinetic models using global 
      sensitivity analysis: diazepam case study.
PG  - 1-27
AB  - There are situations in drug development where one may wish to reduce the 
      dimensionality and complexity of whole body physiologically based pharmacokinetic 
      models. A technique for formal reduction of such models, based on global 
      sensitivity analysis, is suggested. Using this approach mean and variance of 
      tissue(s) and/or blood concentrations are preserved in the reduced models. 
      Extended Fourier amplitude sensitivity test (FAST), a global sensitivity 
      technique, takes a sampling approach, acknowledging parameter variability and 
      uncertainty, to calculate the impact of parameters on concentration variance. We 
      used existing literature rules for formal model reduction to identify all 
      possible smaller dimensionally models. To discriminate among those competing 
      mechanistic models extended FAST was used, whereby we treated model structural 
      uncertainty as another factor contributing to the overall uncertainty. A 
      previously developed 14 compartment whole body physiologically based model for 
      diazepam disposition in rat was reduced to three alternative reduced models, with 
      preserved arterial mean and variance concentration profiles.
FAU - Gueorguieva, Ivelina
AU  - Gueorguieva I
AD  - Centre for Applied Pharmacokinetic Research, School of Pharmacy and 
      Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester, M13 
      9PL, UK. ivelina.gueorguieva@manchester.ac.uk
FAU - Nestorov, Ivan A
AU  - Nestorov IA
FAU - Rowland, Malcolm
AU  - Rowland M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20051220
PL  - United States
TA  - J Pharmacokinet Pharmacodyn
JT  - Journal of pharmacokinetics and pharmacodynamics
JID - 101096520
RN  - Q3JTX2Q7TU (Diazepam)
SB  - IM
MH  - Animals
MH  - Diazepam/administration & dosage/*pharmacokinetics
MH  - *Models, Biological
MH  - *Physiology
MH  - Rats
MH  - Sensitivity and Specificity
MH  - Tissue Distribution
EDAT- 2005/12/22 09:00
MHDA- 2006/06/20 09:00
CRDT- 2005/12/22 09:00
PHST- 2004/12/01 00:00 [received]
PHST- 2005/05/11 00:00 [accepted]
PHST- 2005/12/22 09:00 [pubmed]
PHST- 2006/06/20 09:00 [medline]
PHST- 2005/12/22 09:00 [entrez]
AID - 10.1007/s10928-005-0004-8 [doi]
PST - ppublish
SO  - J Pharmacokinet Pharmacodyn. 2006 Feb;33(1):1-27. doi: 10.1007/s10928-005-0004-8. 
      Epub 2005 Dec 20.