A systems biomedicine approach for chronotherapeutics optimization: focus on the anticancer drug irinotecan.

Most physiological functions in mammals display rhythms of period around 24 h, also called circadian rhythms. This temporal organization of the organism results in variations in the toxicity and efficacy of many antidrugs with respect to their circadian time of administration. Recent experimental and clinical results support the need of personnalizing the chronomodulated administration pattern according to the patient genetic and circadian profile. We propose here a systems biomedicine approach for the optimization of the circadian delivery of irinotecan (CPT11), an anticancer drug approved for the treatment of colorectal cancer. First, CPT11 pharmacokinetics-pharmacodynamics (PK-PD) has been experimentally studied in Caco-2 colon cancer cell cultures. After cell synchronization, circadian rhythms with a period of 26 h 50 (SD 63 min) were observed as well as circadian variations in the protein amount of DNA-bound topoisomerase 1 in presence of CPT11, a marker of the drug PD. A mathematical model of CPT11 molecular PK-PD was then designed, fitted to experimental data and used in therapeutic optimization procedures. We adopted the therapeutics strategy of maximizing efficacy in non-synchronized cells, considered as cancer cells, under a constraint of maximum toxicity in synchronized cells, representing healthy ones. For any dose of CPT11, optimal expoure durations varied from 3h40 to 7h10. Optimal schemes started between CT2h10 and CT2h30, a time interval corresponding to 1 h 30 to 1 h 50 before the nadir of CPT11 bioactivation rhythm in healthy cells. The second step of our approach has consisted in optimizing CPT11 administration in mice. Within the European project TEMPO, CPT11 chronotoxicity has been studied in mice and three classes have been determined with regards to CPT11 best circadian time of administration (i.e. the time which induces the minimal toxicity). We have developed a whole-body physiologically-based model of CPT11 PK-PD based on the previous in vitro study, which aims at identifying molecular biomarkers which could discriminate between the mouse classes and at designing optimal chronomodu-lated infusion scheme for each of them. Parameters of the model have been estimated for B6D2F1 male mice (chronotoxicity class 2) by fitting available data on tissular PK for two different circadian times of administration and on circadian rhythms of relevant proteins. The same parameter estimation is in progress for the two other classes, which will allow the comparaison of the three parameter sets in order to identify molecular differences between the classes. Moreover, optimization algorithms will be applied to the data-calibrated model to design theoretically optimal chronomodulated scheme of administration. In a clinical perspective, this whole-body model of CPT11 PK-PD designed for mice will be adapted to humans by keeping its main structure and resizing parameter values. This will provide clinicians with a new tool towards the personalization of CPT11 administration according to the patient genetic and circadian profile