Kinetic-Pharmacodynamic Model of Chemotherapy-Induced Peripheral Neuropathy in Patients with Metastatic Breast Cancer Treated with Paclitaxel, Nab-Paclitaxel, or Ixabepilone: CALGB 40502 (Alliance)

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity caused by several chemotherapeutic agents. Currently, CIPN is managed by empirical dose modifications at the discretion of the treating physician. The goal of this research is to quantitate the dose-CIPN relationship to inform the optimal strategies for dose modification. Data were obtained from the Cancer and Leukemia Group B (CALGB) 40502 trial, a randomized phase III trial of paclitaxel vs. nab-paclitaxel vs. ixabepilone as first-line chemotherapy for locally recurrent or metastatic breast cancer. CIPN was measured using a subset of the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group Neurotoxicity (FACT-GOG-NTX) scale. A kinetic-pharmacodynamic (K-PD) model was utilized to quantitate the dose-CIPN relationship simultaneously for the three drugs. Indirect response models with linear and S_max drug effects were evaluated. The model was evaluated by comparing the predicted proportion of patients with CIPN (score ≥8 or score ≥12) to the observed proportion. An indirect response model with linear drug effect was able to describe the longitudinal CIPN data reasonably well. The proportion of patients that were falsely predicted to have CIPN or were falsely predicted not to have CIPN was 20% or less at any cycle. The model will be utilized to identify an early time point that can predict CIPN at later time points. This strategy will be utilized to inform dose adjustments to prospectively manage CIPN. Clinicaltrials.gov ID: NCT00785291.

Keywords: CIPN; K-PD model; ixabepilone; nab-paclitaxel; paclitaxel.

Figure 1

Diagrammatic representation of the K-PD model. A(t): the amount of drug in the virtual compartment at time t, KDE: elimination rate constant from the virtual compartment, IR(t):the virtual infusion rate at time t, K_in: the zero order rate for the appearance of CIPN symptoms and K_out: the first order rate constant for the disappearance of CIPN symptoms.

Figure 2

Observed time course of CIPN score for paclitaxel, nab-paclitaxel and ixabepilone. The numbers on the top represent the number of observations at each cycle.

Figure 3

Time to first CIPN based on different CIPN score cut-offs.

Figure 4A

Model predicted time course of representative subjects for paclitaxel. Solid black circles represent observed data; blue and black lines represent individual and population predicted CIPN score, respectively. Numbers in red represent dose administered on day 1, 8 and 15 of a cycle.

Figure 4B

Model predicted time course of representative subjects for nab-paclitaxel. Solid black circles represent observed data; blue and black lines represent individual and population predicted CIPN score, respectively. Numbers in red represent dose administered on days 1, 8 and 15 of a cycle.

Figure 4C

Model predicted time course of representative subjects for ixabepilone. Solid black circles represent observed data; blue and black lines represent individual and population predicted CIPN score, respectively. Numbers in red represent dose administered on days 1, 8 and 15 of a cycle.

Figure 5

Model predicted time course of CIPN score for paclitaxel (90 mg/m²), nab-paclitaxel (150 mg/m²) and ixabepilone (16 mg/m²) administered for 7 cycles to a typical patient with BSA of 1.8 m². The solid black vertical line denotes day of last dose. The solid red, blue and black lines are mean predicted CIPN scores and the dotted lines denote 90% confidence intervals derived from bootstrap.

Figure 6

Model evaluation using individual post-hoc parameter estimates for CIPN cutoff of ≥8. Red squares, blue circles and black triangles represent paclitaxel (PAC), nab-paclitaxel (NPAC) and ixabepilone (IXA), respectively. Discord1&2: Discordant pairs (Discord1: Observed CIPN score <8 while predicted CIPN score is ≥8; Discord2: Observed CIPN score ≥8 while predicted CIPN score is < 8); Concord1&2: Concordant pairs (Concord1: Both observed and predicted CIPN score ≥ 8; Concord2: Both observed and predicted CIPN score < 8).