PMID- 32862303
OWN - NLM
STAT- MEDLINE
DCOM- 20210524
LR  - 20240329
IS  - 1550-7416 (Electronic)
IS  - 1550-7416 (Linking)
VI  - 22
IP  - 5
DP  - 2020 Aug 30
TI  - Inter-compound and Intra-compound Global Sensitivity Analysis of a Physiological 
      Model for Pulmonary Absorption of Inhaled Compounds.
PG  - 116
LID - 10.1208/s12248-020-00499-0 [doi]
LID - 116
AB  - In recent years, global sensitivity analysis (GSA) has gained interest in 
      physiologically based pharmacokinetics (PBPK) modelling and simulation from 
      pharmaceutical industry, regulatory authorities, and academia. With the case 
      study of an in-house PBPK model for inhaled compounds in rats, the aim of this 
      work is to show how GSA can contribute in PBPK model development and daily use. 
      We identified two types of GSA that differ in the aims and, thus, in the 
      parameter variability: inter-compound and intra-compound GSA. The inter-compound 
      GSA aims to understand which are the parameters that mostly influence the 
      variability of the metrics of interest in the whole space of the drugs' 
      properties, and thus, it is useful during the model development. On the other 
      hand, the intra-compound GSA aims to highlight how much the uncertainty 
      associated with the parameters of a given drug impacts the uncertainty in the 
      model prediction and so, it is useful during routine PBPK use. In this work, 
      inter-compound GSA highlighted that dissolution- and formulation-related 
      parameters were mostly important for the prediction of the fraction absorbed, 
      while the permeability is the most important parameter for lung AUC and MRT. 
      Intra-compound GSA highlighted that, for all the considered compounds, the 
      permeability was one of the most important parameters for lung AUC, MRT and 
      plasma MRT, while the extraction ratio and the dose for the plasma AUC. GSA is a 
      crucial instrument for the quality assessment of model-based inference; for this 
      reason, we suggest its use during both PBPK model development and use.
FAU - Melillo, Nicola
AU  - Melillo N
AD  - Laboratory of Bioinformatics, Mathematical Modelling and Synthetic Biology, 
      Department of Electrical, Computer and Biomedical Engineering, Universita degli 
      Studi di Pavia, Via Ferrata 5, I-27100, Pavia, Italy.
FAU - Grandoni, Silvia
AU  - Grandoni S
AD  - Laboratory of Bioinformatics, Mathematical Modelling and Synthetic Biology, 
      Department of Electrical, Computer and Biomedical Engineering, Universita degli 
      Studi di Pavia, Via Ferrata 5, I-27100, Pavia, Italy.
FAU - Cesari, Nicola
AU  - Cesari N
AD  - Pharmacokinetics, Biochemistry and Metabolism Department, Chiesi Farmaceutici 
      S.p.A., Parma, Italy.
FAU - Brogin, Giandomenico
AU  - Brogin G
AD  - Pharmacokinetics, Biochemistry and Metabolism Department, Chiesi Farmaceutici 
      S.p.A., Parma, Italy.
FAU - Puccini, Paola
AU  - Puccini P
AD  - Pharmacokinetics, Biochemistry and Metabolism Department, Chiesi Farmaceutici 
      S.p.A., Parma, Italy.
FAU - Magni, Paolo
AU  - Magni P
AUID- ORCID: 0000-0002-8931-4676
AD  - Laboratory of Bioinformatics, Mathematical Modelling and Synthetic Biology, 
      Department of Electrical, Computer and Biomedical Engineering, Universita degli 
      Studi di Pavia, Via Ferrata 5, I-27100, Pavia, Italy. paolo.magni@unipv.it.
LA  - eng
PT  - Evaluation Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200830
PL  - United States
TA  - AAPS J
JT  - The AAPS journal
JID - 101223209
SB  - IM
MH  - Administration, Inhalation
MH  - Animals
MH  - *Models, Theoretical
MH  - Rats
MH  - *Respiratory Tract Absorption
PMC - PMC7456635
OTO - NOTNLM
OT  - PBPK
OT  - global sensitivity analysis
OT  - inter-compound
OT  - intra-compound
OT  - model assessment
OT  - model building
OT  - pulmonary absorption model
EDAT- 2020/08/31 06:00
MHDA- 2021/05/25 06:00
PMCR- 2020/08/30
CRDT- 2020/08/31 06:00
PHST- 2020/04/26 00:00 [received]
PHST- 2020/08/06 00:00 [accepted]
PHST- 2020/08/31 06:00 [entrez]
PHST- 2020/08/31 06:00 [pubmed]
PHST- 2021/05/25 06:00 [medline]
PHST- 2020/08/30 00:00 [pmc-release]
AID - 10.1208/s12248-020-00499-0 [pii]
AID - 499 [pii]
AID - 10.1208/s12248-020-00499-0 [doi]
PST - epublish
SO  - AAPS J. 2020 Aug 30;22(5):116. doi: 10.1208/s12248-020-00499-0.