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A model based analysis of IPEC dosing of paclitaxel in rats

Pieter Colin UGent, Lieselotte De Smet, Chris Vervaet UGent, Jean Paul Remon UGent, Wim Ceelen UGent, Jan Van Bocxlaer UGent, Koen Boussery UGent and An Vermeulen UGent (2014) PHARMACEUTICAL RESEARCH. 31(10). p.2876-2886
abstract
Purpose: A strong pharmacokinetic rational exists for the use of (Hyperthermic) Intraperitoneal Perioperative Chemotherapy in peritoneal carcinomatosis. However, controversy remains regarding the optimal treatment strategies. Paclitaxel is believed to be a good compound for IPEC treatment because of its favourable pharmacokinetic properties. Methods: Rat experiments were set up to gain insight in PTX’s pharmacokinetics and pharmacodynamics after IPEC treatment with Taxol®. Afterwards a Pharmacokinetic—Pharmacodynamic model was developed, that concurrently describes plasma and tumour exposure post IPEC dosing. Moreover, the developed model adequately describes the time-course of tumour apoptosis as well as the treatment effect on tumour volume. Results: We show that the complex absorption processes underlying PTX absorption from the peritoneal cavity post IPEC dosing, give rise to a markedly non-linear dose response relationship. Furthermore, we show that, in order to optimize treatment efficiency whilst concurrently minimizing the possibility of systemic toxicities, lowering the dose and extending exposure to the cytotoxic solution is the way forward. Conclusions: Based on the close resemblance between tumour exposure in our animal model and tumour exposure in patients treated under similar conditions, we hypothesise that, according to our findings in the rat, in the treatment of PC using IPEC administration of PTX, less is truly more.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
PKPD, Paclitaxel, Tumor, Peritoneal carcinomatosis, IPEC, INTRAPERITONEAL THERAPY, ALTERED PHARMACOKINETICS, TISSUE PENETRATION, SOLID TUMORS, CANCER, DETERMINANTS, ACCUMULATION, RETENTION, TRANSPORT, NONMEM, CHEMOTHERAPY
journal title
PHARMACEUTICAL RESEARCH
Pharm. Res.
volume
31
issue
10
pages
2876 - 2886
Web of Science type
Article
Web of Science id
000343889300028
JCR category
CHEMISTRY, MULTIDISCIPLINARY
JCR impact factor
3.42 (2014)
JCR rank
39/157 (2014)
JCR quartile
1 (2014)
ISSN
0724-8741
DOI
10.1007/s11095-014-1384-5
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
4400170
handle
http://hdl.handle.net/1854/LU-4400170
date created
2014-05-26 16:13:39
date last changed
2016-12-19 15:43:02
@article{4400170,
  abstract     = {Purpose: A strong pharmacokinetic rational exists for the use of (Hyperthermic) Intraperitoneal Perioperative Chemotherapy in peritoneal carcinomatosis. However, controversy remains regarding the optimal treatment strategies. Paclitaxel is believed to be a good compound for IPEC treatment because of its favourable pharmacokinetic properties.
Methods: Rat experiments were set up to gain insight in PTX{\textquoteright}s pharmacokinetics and pharmacodynamics after IPEC treatment with Taxol{\textregistered}. Afterwards a Pharmacokinetic---Pharmacodynamic model was developed, that concurrently describes plasma and tumour exposure post IPEC dosing. Moreover, the developed model adequately describes the time-course of tumour apoptosis as well as the treatment effect on tumour volume.
Results: We show that the complex absorption processes underlying PTX absorption from the peritoneal cavity post IPEC dosing, give rise to a markedly non-linear dose response relationship. Furthermore, we show that, in order to optimize treatment efficiency whilst concurrently minimizing the possibility of systemic toxicities, lowering the dose and extending exposure to the cytotoxic solution is the way forward.
Conclusions: Based on the close resemblance between tumour exposure in our animal model and tumour exposure in patients treated under similar conditions, we hypothesise that, according to our findings in the rat, in the treatment of PC using IPEC administration of PTX, less is truly more.},
  author       = {Colin, Pieter and De Smet, Lieselotte and Vervaet, Chris and Remon, Jean Paul and Ceelen, Wim and Van Bocxlaer, Jan and Boussery, Koen and Vermeulen, An},
  issn         = {0724-8741},
  journal      = {PHARMACEUTICAL RESEARCH},
  keyword      = {PKPD,Paclitaxel,Tumor,Peritoneal carcinomatosis,IPEC,INTRAPERITONEAL THERAPY,ALTERED PHARMACOKINETICS,TISSUE PENETRATION,SOLID TUMORS,CANCER,DETERMINANTS,ACCUMULATION,RETENTION,TRANSPORT,NONMEM,CHEMOTHERAPY},
  language     = {eng},
  number       = {10},
  pages        = {2876--2886},
  title        = {A model based analysis of IPEC dosing of paclitaxel in rats},
  url          = {http://dx.doi.org/10.1007/s11095-014-1384-5},
  volume       = {31},
  year         = {2014},
}

Chicago
Colin, Pieter, Lieselotte De Smet, Chris Vervaet, Jean Paul Remon, Wim Ceelen, Jan Van Bocxlaer, Koen Boussery, and An Vermeulen. 2014. “A Model Based Analysis of IPEC Dosing of Paclitaxel in Rats.” Pharmaceutical Research 31 (10): 2876–2886.
APA
Colin, Pieter, De Smet, L., Vervaet, C., Remon, J. P., Ceelen, W., Van Bocxlaer, J., Boussery, K., et al. (2014). A model based analysis of IPEC dosing of paclitaxel in rats. PHARMACEUTICAL RESEARCH, 31(10), 2876–2886.
Vancouver
1.
Colin P, De Smet L, Vervaet C, Remon JP, Ceelen W, Van Bocxlaer J, et al. A model based analysis of IPEC dosing of paclitaxel in rats. PHARMACEUTICAL RESEARCH. 2014;31(10):2876–86.
MLA
Colin, Pieter, Lieselotte De Smet, Chris Vervaet, et al. “A Model Based Analysis of IPEC Dosing of Paclitaxel in Rats.” PHARMACEUTICAL RESEARCH 31.10 (2014): 2876–2886. Print.