PMID- 37826938
OWN - NLM
STAT- MEDLINE
DCOM- 20231115
LR  - 20231115
IS  - 1950-6007 (Electronic)
IS  - 0753-3322 (Linking)
VI  - 168
DP  - 2023 Dec
TI  - A physiologically-based pharmacokinetic model for predicting doxorubicin 
      disposition in multiple tissue levels and quantitative toxicity assessment.
PG  - 115636
LID - S0753-3322(23)01434-8 [pii]
LID - 10.1016/j.biopha.2023.115636 [doi]
AB  - Doxorubicin is a widely-used chemotherapeutic drug, however its high toxicity 
      poses a significant challenge for its clinical use. To address this issue, a 
      physiologically-based pharmacokinetic (PBPK) model was implemented to 
      quantitatively assess doxorubicin toxicity at cellular scale. Due to its unique 
      pharmacokinetic behavior (e.g. high volume of distribution and affinity to 
      extra-plasma tissue compartments), we proposed a modified PBPK model structure 
      and developed the model with multispecies extrapolation to compensate for the 
      limitation of obtaining clinical tissue data. Our model predicted the disposition 
      of doxorubicin in multiple tissues including clinical tissue data with an overall 
      absolute average fold error (AAFE) of 2.12. The model's performance was further 
      validated with 8 clinical datasets in combined with intracellular doxorubicin 
      concentration with an average AAFE of 1.98. To assess the potential cellular 
      toxicity, toxicity levels and area under curve (AUC) were defined for different 
      dosing regimens in toxic and non-toxic scenarios. The cellular concentrations of 
      doxorubicin in multiple organ sites associated with commonly observed adverse 
      effects (AEs) were simulated and calculated the AUC for quantitative assessments. 
      Our findings supported the clinical dosing regimen of 75 mg/m(2) with a 21-day 
      interval and suggest that slow infusion and separated single high doses may lower 
      the risk of developing AEs from a cellular level, providing valuable insights for 
      the risk assessment of doxorubicin chemotherapy. In conclusion, our work 
      highlights the potential of PBPK modelling to provide quantitative assessments of 
      cellular toxicity and supports the use of clinical dosing regimens to mitigate 
      the risk of adverse effects.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Masson SAS.. All rights 
      reserved.
FAU - Chao, Fang-Ching
AU  - Chao FC
AD  - CNRS UMR 8612, Institut Galien Paris-Saclay, Universite Paris-Saclay, Orsay 
      91400, France.
FAU - Manaia, Eloisa Berbel
AU  - Manaia EB
AD  - CNRS UMR 8612, Institut Galien Paris-Saclay, Universite Paris-Saclay, Orsay 
      91400, France.
FAU - Ponchel, Gilles
AU  - Ponchel G
AD  - CNRS UMR 8612, Institut Galien Paris-Saclay, Universite Paris-Saclay, Orsay 
      91400, France. Electronic address: gilles.ponchel@universite-paris-saclay.fr.
FAU - Hsieh, Chien-Ming
AU  - Hsieh CM
AD  - School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, 
      Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of 
      Pharmacy, Taipei Medical University, Taipei 11031, Taiwan. Electronic address: 
      cmhsieh@tmu.edu.tw.
LA  - eng
PT  - Journal Article
DEP - 20231010
PL  - France
TA  - Biomed Pharmacother
JT  - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
JID - 8213295
RN  - 80168379AG (Doxorubicin)
SB  - IM
MH  - Humans
MH  - *Models, Biological
MH  - Doxorubicin/pharmacokinetics
MH  - *Drug-Related Side Effects and Adverse Reactions
MH  - Area Under Curve
OTO - NOTNLM
OT  - Disposition
OT  - Doxorubicin
OT  - Interspecies extrapolation
OT  - Physiologically-based pharmacokinetics
OT  - Quantitative pharmacology
OT  - Toxicity
COIS- Declaration of Competing Interest There are none.
EDAT- 2023/10/13 00:42
MHDA- 2023/11/15 06:43
CRDT- 2023/10/12 18:05
PHST- 2023/07/20 00:00 [received]
PHST- 2023/09/22 00:00 [revised]
PHST- 2023/10/03 00:00 [accepted]
PHST- 2023/11/15 06:43 [medline]
PHST- 2023/10/13 00:42 [pubmed]
PHST- 2023/10/12 18:05 [entrez]
AID - S0753-3322(23)01434-8 [pii]
AID - 10.1016/j.biopha.2023.115636 [doi]
PST - ppublish
SO  - Biomed Pharmacother. 2023 Dec;168:115636. doi: 10.1016/j.biopha.2023.115636. Epub 
      2023 Oct 10.