Evaluating the indotecan-neutropenia relationship in patients with solid tumors by population pharmacokinetic modeling and sigmoidal Emax regressions

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01051635 NCT01794104.

Keywords: Indotecan; LMP400; PK-PD; Pharmacodynamics; Population pharmacokinetics.

Fig. 1

Diagnostic plots for the final population-based pharmacokinetic model of indotecan in study NCI 8273 and NCI 9430. Observed plasma indotecan concentrations (μg/L) versus population-predicted (A) and individual-predicted (B) concentrations. Conditional weighted residuals versus time after dose (C) and individual weighted residuals vs individual predicted concentration (D). Red lines represent the result of a loess smoother

Fig. 2

Quantitative predictive check for dose-normalized parameters, ${\text{AUC}}_{0-\infty }$ (h/L) and $C_{\max }$(L⁻¹), determined using first dose data for both the daily cohort (A, C, E, G) and the weekly cohort (B, D, F, H). Histograms A-D display the distribution of median dose-normalized parameters from 1000 simulated datasets. Histograms E-H display the distribution of all dose-normalized parameters for all simulated subjects. The solid blue lines represent the observed median of both dose-normalized ${\text{AUC}}_{0-\infty }$ and $C_{\max }$, and the black dotted lines represent the 5th, 50th, and 95th percentile of the simulated dose normalized ${\text{AUC}}_{0-\infty }$ and $C_{\max }$

Fig. 3

Comparison of the predicted indotecan–neutropenia relationship for both dosing groups from the final sigmoidal $E_{\max }$ model with observations overlayed. Black solid points represent quartiles of observed average concentration for the population (n = 20 and n = 21 for the daily and weekly cohorts, respectively) and the associated average observed percent reduction in ANC from baseline. Black solid lines represent error bars for each quartile. Dark blue and dark green solid lines represent the median predicted relationship, dark blue and dark green shaded areas represent the confidence interval of response without residual variability, and the light blue and light green shaded areas represent prediction interval of response with residual variability