Modeling oxaliplatin drug delivery to circadian rhythms in drug metabolism and host tolerance

To make possible the design of optimal (circadian and other period) time-scheduled regimens for cytotoxic drug delivery by intravenous infusion, a pharmacokinetic–pharmacodynamic (PK–PD, with circadian periodic drug dynamics) model of chemotherapy on a population of tumor cells and its tolerance by a population of fast renewing healthy cells is presented. The application chosen for identification of the model parameters is the treatment by oxaliplatin of Glasgow osteosarcoma, a murine tumor, and the healthy cell population is the jejunal mucosa, which is the main target of oxaliplatin toxicity in mice. The model shows the advantage of a periodic time-scheduled regimen, compared to the conventional continuous constant infusion of the same daily dose, when the biological time of peak infusion is correctly chosen. Furthermore, it is well adapted to using mathematical optimization methods of drug infusion flow, choosing tumor population minimization as the objective function and healthy tissue preservation as a constraint. Such a constraint is in clinical settings tunable by physicians by taking into account the patient's state of health.