PMID- 32545464
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200928
IS  - 2077-0383 (Print)
IS  - 2077-0383 (Electronic)
IS  - 2077-0383 (Linking)
VI  - 9
IP  - 6
DP  - 2020 Jun 12
TI  - A Minimal PKPD Interaction Model for Evaluating Synergy Effects of Combined NSCLC 
      Therapies.
LID - 10.3390/jcm9061832 [doi]
LID - 1832
AB  - This paper introduces a mathematical compartmental formulation of dose-effect 
      synergy modelling for multiple therapies in non small cell lung cancer (NSCLC): 
      antiangiogenic, immuno- and radiotherapy. The model formulates the dose-effect 
      relationship in a unified context, with tumor proliferating rates and necrotic 
      tissue volume progression as a function of therapy management profiles. The model 
      accounts for inter- and intra-response variability by using surface model 
      response terms. Slow acting peripheral compartments such as fat and muscle for 
      drug distribution are not modelled. This minimal pharmacokinetic-pharmacodynamic 
      (PKPD) model is evaluated with reported data in mice from literature. A 
      systematic analysis is performed by varying only radiotherapy profiles, while 
      antiangiogenesis and immunotherapy are fixed to their initial profiles. Three 
      radiotherapy protocols are selected from literature: (1) a single dose 5 Gy once 
      weekly; (2) a dose of 5 Gy x 3 days followed by a 2 Gy x 3 days after two weeks 
      and (3) a dose of 5 Gy + 2 x 0.075 Gy followed after two weeks by a 2 Gy + 2 x 
      0.075 Gy dose. A reduction of 28% in tumor end-volume after 30 days was observed 
      in Protocol 2 when compared to Protocol 1. No changes in end-volume were observed 
      between Protocol 2 and Protocol 3, this in agreement with other literature 
      studies. Additional analysis on drug interaction suggested that higher synergy 
      among drugs affects up to three-fold the tumor volume (increased synergy leads to 
      significantly lower growth ratio and lower total tumor volume). Similarly, 
      changes in patient response indicated that increased drug resistance leads to 
      lower reduction rates of tumor volumes, with end-volume increased up to 25-30%. 
      In conclusion, the proposed minimal PKPD model has physiological value and can be 
      used to study therapy management protocols and is an aiding tool in the clinical 
      decision making process. Although developed with data from mice studies, the 
      model is scalable to NSCLC patients.
FAU - Ionescu, Clara Mihaela
AU  - Ionescu CM
AUID- ORCID: 0000-0001-7685-035X
AD  - Research Group of Dynamical Systems and Control, Ghent University, Tech Lane 
      Science Park 125, 9052 Ghent, Belgium.
AD  - EEDT-Core Lab on Decision and Control, Flanders Make Consortium, Tech Lane 
      Science Park 131, 9052 Ghent, Belgium.
AD  - Department of Automatic Control, Technical University of Cluj Napoca, 
      Memorandumului 28, 400114 Cluj-Napoca, Romania.
FAU - Ghita, Maria
AU  - Ghita M
AUID- ORCID: 0000-0002-3463-5173
AD  - Research Group of Dynamical Systems and Control, Ghent University, Tech Lane 
      Science Park 125, 9052 Ghent, Belgium.
AD  - EEDT-Core Lab on Decision and Control, Flanders Make Consortium, Tech Lane 
      Science Park 131, 9052 Ghent, Belgium.
FAU - Copot, Dana
AU  - Copot D
AUID- ORCID: 0000-0002-6010-830X
AD  - Research Group of Dynamical Systems and Control, Ghent University, Tech Lane 
      Science Park 125, 9052 Ghent, Belgium.
AD  - EEDT-Core Lab on Decision and Control, Flanders Make Consortium, Tech Lane 
      Science Park 131, 9052 Ghent, Belgium.
FAU - Derom, Eric
AU  - Derom E
AD  - Department of Respiratory Medicine, Ghent University Hospital, C. Heymanslaan 10, 
      9000 Gent, Belgium.
FAU - Verellen, Dirk
AU  - Verellen D
AD  - Iridium Cancer Network-GZA Hospitals Sint Augustinus, Department of Medical 
      Physics Radiotherapy, Oosterveldlaan 24, 2610 Wilrijk, Belgium.
AD  - Radiotherapy Department, Faculty of Medicine and Health Sciences, Antwerp 
      University, Universiteitsplein 1, 2610 Wilrijk, Belgium.
LA  - eng
GR  - 01J01619/Bijzonder Onderzoeksfonds/
GR  - 01D15919/Bijzonder Onderzoeksfonds/
GR  - 12X6819N/Fonds Wetenschappelijk Onderzoek/
PT  - Journal Article
DEP - 20200612
PL  - Switzerland
TA  - J Clin Med
JT  - Journal of clinical medicine
JID - 101606588
PMC - PMC7356515
OTO - NOTNLM
OT  - anomalous diffusion
OT  - antiangiogenic therapy
OT  - fractal kinetics
OT  - immunotherapy
OT  - lung cancer
OT  - mathematical modelling
OT  - mouse data
OT  - multiple therapy
OT  - radiotherapy
OT  - synergy
OT  - variability
COIS- The authors declare no conflict of interest.
EDAT- 2020/06/18 06:00
MHDA- 2020/06/18 06:01
PMCR- 2020/06/12
CRDT- 2020/06/18 06:00
PHST- 2020/04/20 00:00 [received]
PHST- 2020/06/05 00:00 [revised]
PHST- 2020/06/09 00:00 [accepted]
PHST- 2020/06/18 06:00 [entrez]
PHST- 2020/06/18 06:00 [pubmed]
PHST- 2020/06/18 06:01 [medline]
PHST- 2020/06/12 00:00 [pmc-release]
AID - jcm9061832 [pii]
AID - jcm-09-01832 [pii]
AID - 10.3390/jcm9061832 [doi]
PST - epublish
SO  - J Clin Med. 2020 Jun 12;9(6):1832. doi: 10.3390/jcm9061832.