Optimal Design Applied to Hematological Toxicity-Induced Anticancer Treatment

Anticancer regimens are often a delicate compromise between dose intensity and acceptable toxicity, for example neutropenia. The aim of the present study was to develop a theoretical framework using optimal design theory to select the optimal dosing and sampling based on several criteria derived from the predicted neutrophil counts. A semi-physiological PK/PD model for docetaxel's hematological toxicity was used to determine the population typical nadir value of absolute neutrophil count and the time of occurrence of the nadir. An optimization on both time and size of dosing was performed in PopED v.2.11.The optimizations maximized the expected nadir value given a set of clinical criteria using a penalty function. Sampling schedules were also optimized to allow for model identification of the nadir value using D- , C-, MAP-optimal criteria and by using a Sample Reuse Simulation approach. Optimized dosing schedules were found to expose fewer patients to grade 4 neutropenia and total dose could be further increased with recommended dosing intervals. Predicted population nadir was more precisely estimated with a D-optimal design while sampling a true nadir value was more frequently done with a design derived from a Sample Reuse Simulation method. Optimal design methodology can be applied for toxicity monitoring within clinical constraints in oncology studies.