Pharmacokinetics and pharmacodynamics-based mathematical modeling identifies an optimal protocol for metronomic chemotherapy

Metronomic chemotherapy is usually associated with better tolerance than conventional chemotherapy, and encouraging response rates have been reported in various settings. However, clinical development of metronomic chemotherapy has been hampered by a number of limitations, including the vagueness of its definition and the resulting empiricism in protocol design. In this study, we developed a pharmacokinetic/pharmacodynamic (PK/PD) mathematical model that identifies in silico the most effective administration schedule for gemcitabine monotherapy. This model is based upon four biological assumptions regarding the mechanisms of action of metronomic chemotherapy, resulting in a set of 6 minimally parameterized differential equations. Simulations identified daily 0.5-1 mg/kg gemcitabine as an optimal protocol to maximize anti-tumor efficacy. Both metronomic protocols (0.5 and 1 mg/kg/day for 28 days) were evaluated in chemoresistant neuroblastoma-bearing mice and compared with the standard MTD protocol (100 mg/kg once a week for 4 weeks). Systemic exposure to gemcitabine was 14 times lower in the metronomic groups compared with the standard group. Despite this, metronomic gemcitabine significantly inhibited tumor angiogenesis and reduced tumor perfusion and inflammation in vivo, while standard gemcitabine did not. Furthermore, metronomic gemcitabine yielded a 40-50% decrease in tumor mass at the end of treatment as compared to control mice (p=0.002; ANOVA on Ranks with Dunn's Test), while standard gemcitabine failed to significantly reduce tumor growth. Stable disease was maintained in the metronomic groups for up to 2 months after treatment completion (67-72% reduction in tumor growth at study conclusion, p>0.001; ANOVA on Ranks with Dunn's Test). Collectively, our results confirmed the superiority of metronomic protocols in chemoresistant tumors in vivo. <p>MAJOR FINDING: our study demonstrates the potential of PK/PD mathematical modeling to optimize metronomic chemotherapy protocols, which can be tested in non-clinical models and future clinical trials.

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