Publication

A Model Based Analysis of IPEC Dosing of Paclitaxel in Rats

Colin, P., De Smet, L., Vervaet, C., Remon, J-P., Ceelen, W., Van Bocxlaer, J., Boussery, K. & Vermeulen, A., Oct-2014, In : Pharmaceutical Research. 31, 10, p. 2876-2886 11 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • Pieter Colin
  • Lieselotte De Smet
  • Chris Vervaet
  • Jean-Paul Remon
  • Wim Ceelen
  • Jan Van Bocxlaer
  • Koen Boussery
  • An Vermeulen

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 (R). 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.

Original languageEnglish
Pages (from-to)2876-2886
Number of pages11
JournalPharmaceutical Research
Volume31
Issue number10
Publication statusPublished - Oct-2014
Externally publishedYes

    Keywords

  • IPEC, NONMEM, paclitaxel, PKPD, INTRAPERITONEAL THERAPY, ALTERED PHARMACOKINETICS, TISSUE PENETRATION, SOLID TUMORS, CANCER, DETERMINANTS, ACCUMULATION, CHEMOTHERAPY, RETENTION, TRANSPORT

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