A model based analysis of IPEC dosing of paclitaxel in rats.
OBJECTIVE
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.
Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium, Pieter.Colin@ugent.be.
Pieter
P
Colin
Lieselotte
L
De Smet
Chris
C
Vervaet
Jean-Paul
JP
Remon
Wim
W
Ceelen
Jan
J
Van Bocxlaer
Koen
K
Boussery
An
A
Vermeulen
D065567:Absorption, Physiological; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D008954:Models, Biological; D017711:Nonlinear Dynamics; D010051:Ovarian Neoplasms / Q000473:pathology / Q000601:surgery; D017239:Paclitaxel / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary; D011923:Rats, Nude; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D017239:Paclitaxel