Evaluating the indotecan–neutropenia relationship in patients with solid tumors by population pharmacokinetic modeling and sigmoidal E _max regressions

Purpose: This study aimed at characterizing indotecan population pharmacokinetics and explore the indotecan–neutropenia relationship in patients with solid tumors. Methods: Population pharmacokinetics were assessed using nonlinear mixed-effects modeling of concentration data from two first-in-human phase 1 trials evaluating different dosing schedules of indotecan. Covariates were assessed in a stepwise manner. Final model qualification included bootstrap simulation, visual and quantitative predictive checks, and goodness-of-fit. A sigmoidal E_max model was developed to describe the relationship between average concentration and maximum percent neutrophil reduction. Simulations at fixed doses were conducted to determine the mean predicted decrease in neutrophil count for each schedule. Results: 518 concentrations from 41 patients supported a three-compartment pharmacokinetic model. Body weight and body surface area accounted for inter-individual variability of central/peripheral distribution volume and intercompartmental clearance, respectively. Estimated typical population values were CL 2.75 L/h, Q3 46.0 L/h, and V3 37.9 L. The estimated value of Q2 for a typical patient (BSA = 1.96 m²) was 17.3 L/h, while V1 and V2 for a typical patient (WT = 80 kg) was 33.9 L and 132 L. The final sigmoidal E_max model estimated that half-maximal ANC reduction occurs at an average concentration of 1416 µg/L and 1041 µg/L for the daily and weekly regimens, respectively. Simulations of the weekly regimen demonstrated lower percent reduction in ANC compared to the daily regimen at equivalent cumulative fixed doses. Conclusion: The final PK model adequately describes indotecan population pharmacokinetics. Fixed dosing may be justified based on covariate analysis and the weekly dosing regimen may have a reduced neutropenic effect.