Pieter Colin, Lieselotte De Smet, Chris Vervaet, Jean-Paul Remon, Wim Ceelen, Jan Van Bocxlaer, Koen Boussery, An Vermeulen.
Ghent University, Belgium.
Objectives: A strong pharmacokinetic rational exists for the use of (Hyperthermic) Intraperitoneal Perioperative Chemotherapy in peritoneal carcinomatosis [1]. However, controversy remains regarding the optimal treatment strategies. Paclitaxel, a compound only seldomly used in IPEC, is believed to be a good compound for IPEC treatment because of its favourable pharmacokinetic properties [2]. Using a rat model for PC and PKPD modelling, we set out to answer some of the questions regarding IPEC treatment of PC with paclitaxel.
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, lowering the administered dose and prolonging the exposure time should increase treatment efficiency, whilst simultaneously keeping the risk for systemic toxicities minimal.
References:
[1] Dedrick RL, Flessner MF. Pharmacokinetic problems in peritoneal drug administration: Tissue penetration and surface exposure. Journal of the National Cancer Institute 1997 Apr 2;89(7):480-7.
[2] Hasovits C, Clarke S. Pharmacokinetics and Pharmacodynamics of Intraperitoneal Cancer Chemotherapeutics. Clinical Pharmacokinetics 2012;51(4):203-24.
Reference: PAGE 23 (2014) Abstr 3045 [www.page-meeting.org/?abstract=3045]
Poster: Drug/Disease modeling - Oncology