Abstract
Introduction: Improving the efficacy/toxicity balance of anticancer therapy is still challenging, especially in metastatic Non Small Cell Lung Cancer (NSCLC) patients. Metronomic oral Vinorelbine is known to have an activity in NSCLC, but all the studies published thus far were based upon a variety of empirical and suboptimal schedules, with inconsistent results.
Objective: To determine an optimized Vinorelbine metronomic schedule, using advanced mathematical modeling.
Methods: We transposed into mathematical language pharmacokinetics (PK) and pharmacodynamics (PD) efficacy and toxicities issues of oral vinorelbine. All the parameters were calibrated using previous data from preclinical and clinical trials with metronomic vinorelbine. To identify the schedule which achieves higher efficacy on tumor with acceptable tolerance, multiple metronomic modalities have been tested by simulation, using our PK/PD model and Monolix software.
Results: This study describes the development of our mathematical model and its consistency when simulating previously published data. In addition, mathematical modeling showed by simulation that a new metronomic protocol could lead to a better safety and efficacy profile. Whereas most of the trials with oral metronomic vinorelbine used a D1, D3, D5 schedule with a fixed dose of 50 mg, our mathematical model suggested an alternative D1, D2 and D4 innovative schedule with a dynamic intake of 60, 30 and 60 mg, respectively.
Conclusions: Mathematical modeling provides an opportunity to improve efficacy of metronomic regimen. A phase I trial will begin this year to prospectively confirm and to validate clinically this new metronomic protocol in NSCLC patients.
- Copyright ©ERS 2015
