A systems pharmacology approach to optimize the hepatic administration of
oxaliplatin chronotherapy.
Dr Annabelle Ballesta, Prof Pasquale Innominato, Prof Francis Lévi.
Warwick Systems Biology Centre & Medical School, UK
Queen Elisabeth Hospital, Birmingham, UK
Cancer chronotherapeutics- that is administering anticancer drugs following the
patient's biological rhythms over the 24 h span- has nowadays proven its benefit regarding
both toxicities and antitumor efficacy compared to constant administration [1]. Although most
chemotherapies are administered directly into the blood, hepatic administration of antitumor
drugs to colorectal cancer (CRC) patients with liver metastasis have now appeared as a very
promising strategy. The European phase II clinical trial Optiliv successfully tested in CRC
patients the hepatic artery infusion of the anticancer drugs 5-fluorouracil, oxaliplatin and
irinotecan, combined to the targeted molecule cetuximab. Although patient’s survival of this
pilot study was very encouraging, pharmacokinetics (PK) measurements revealed that the
chronomodulated administration schemes utilized for oxaliplatin and irinotecan resulted in
systemic exposure outside of the targeted therapeutic time windows. Hence, this Master
project aims at designing a model of oxaliplatin human chronoPK in order to design the optimal
administration schedule that would induce the desired systemic exposure.
The model will be based on physiology of the whole body and will represent the blood,
the liver, the intestine and the Non Eliminating Tissues (NET). Oxaliplatin transport in-between
those compartments together with the drug irreversible binding to proteins and its renal and
intestinal clearance will be taken into account. Model parameters will be estimated from
available datasets of the blood PK after i) systemic constant drug administration at different
doses, ii) systemic chronomodulated administration, iii) hepatic chromodulated administration
(Optiliv). As a first step, a unique parameter set will be estimated for all cancer patients using
a weighted least-square approach and optimal chronomodulated schemes will be computed
though existing numerical procedures [2]. Next, because recent findings highlight the critical
need of personalizing circadian delivery, a parameter set will be computed for each patient of
the Optiliv trial and personalized drug timing will be designed.
References
1.
2.
Levi, F., et al., Circadian timing in cancer treatments. Annu Rev Pharmacol Toxicol, 2010. 50:
p. 377-421.
Ballesta, A., et al., A combined experimental and mathematical approach for molecularbased optimization of irinotecan circadian delivery. PLoS Comput Biol, 2011. 7(9): p.
e1002143.