A multi‐scale systems pharmacology approach for personalizing irinotecan chronotherapy
Authors: Ballesta Annabelle , Dulong Sandrine , Dallmann Robert , Innominato Pasquale , Lévi Francis 
Published: November 2023

Anticancer chemotherapy personalisation requires to reliably account for the temporal dynamics of molecular pathways of patient's response to drug administration. In a context where clinical molecular data is usually minimal in individual patients, multi‐scale physiologically‐based modelling stands as an adapted solution to describe gene and protein networks ultimately responsible for treatment antitumor efficacy and side effects. As in a multi‐scale pipeline, in vitro systems biology studies allow for the design of whole‐body preclinical rodent models, to be further scaled to patient population data. Calibration of the human model for a given cancer patient according to individual biomarker recordings, patient's genetic background and therapeutic history further allow for the design of theoretically‐optimal personalized chronotherapies, to be validated in dedicated clinical trials.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 efficacy compared to constant administration. However, recent findings highlight the critical need of personalizing circadian delivery. Thus, a multiscale approach is being undertaken for personalising the circadian administration of irinotecan, one of the cornerstones of chemotherapies against digestive cancers. Irinotecan molecular chronopharmacology was studied at the cellular level in an in vitro and in silico investigation. Large transcription rhythms of period T= 28 h 06 min (SD 1 h 41 min) moderated drug bioactivation, detoxification, transport, and target in synchronized Caco‐2 colorectal cancer cell cultures. These molecular rhythms translated into statistically significant changes according to drug timing in irinotecan pharmacokinetics, pharmacodynamics, and drug‐induced apoptosis. Clock silencing through siBMAL1 exposure ablated all the chronopharmacology mechanisms. Mathematical modeling highlighted circadian bioactivation and detoxification as the most critical determinants of irinotecan chronopharmacology (Dulong, Mol Canc Ther, 2015).Next, a mouse investigation allowed for the identification of three classes showing different circadian pattern in irinotecan chronoPK, and intestinal and blood chronotoxicity (Ahowesso, Chronobiol Int, 2011). These in vitro and in vivo studies were used for the design of a mathematical model of the drug whole‐body chronoPK‐PD in mice. Finally, a human model has been developed through a scale‐up of the mouse model integrating several clinical databases of patients under irinotecan‐based chemotherapy (PK time‐concentration profiles, toxicities and efficacy during systemic or hepatic drug administration given as constant or chronomodulated infusion, Lévi, Annu Rev Pharmacol Toxicol, 2010; Lévi, Annals of Oncology, 2015). This model is then utilized to design theoretically‐optimal irinotecan chronotherapies for individual patients.