The AAPS Journal

, Volume 19, Issue 5, pp 1411–1423 | Cite as

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

  • Shailly Mehrotra
  • Manish R. Sharma
  • Elizabeth Gray
  • Kehua Wu
  • William T. Barry
  • Clifford Hudis
  • Eric P. Winer
  • Alan P. Lyss
  • Deborah L. Toppmeyer
  • Alvaro Moreno-Aspitia
  • Thomas E. Lad
  • Mario Valasco
  • Beth Overmoyer
  • Hope Rugo
  • Mark J. Ratain
  • Jogarao V. GobburuEmail author
Research Article


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 Smax 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. ID: NCT00785291


CIPN ixabepilone K-PD model nab-paclitaxel paclitaxel 


Compliance with Ethical Standards


Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA031946, U10CA033601, U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology), U10CA025224, U10CA032291, U10CA041287, U10CA077651, U10CA108068, U10CA138561, U10CA180790, U10CA180791, 5UG1CA189830, U10CA180836, and U10CA180867. Manish R. Sharma was also supported by K12CA139160 from the National Cancer Institute, by a Young Investigator Award from the Cancer Research Foundation, and by K23GM112128 from the National Institute of General Medical Sciences of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Supplementary material

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Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  • Shailly Mehrotra
    • 1
  • Manish R. Sharma
    • 2
  • Elizabeth Gray
    • 3
  • Kehua Wu
    • 4
  • William T. Barry
    • 5
  • Clifford Hudis
    • 6
  • Eric P. Winer
    • 7
  • Alan P. Lyss
    • 8
  • Deborah L. Toppmeyer
    • 9
  • Alvaro Moreno-Aspitia
    • 10
  • Thomas E. Lad
    • 11
  • Mario Valasco
    • 12
  • Beth Overmoyer
    • 7
  • Hope Rugo
    • 13
  • Mark J. Ratain
    • 2
  • Jogarao V. Gobburu
    • 1
    • 14
    Email author
  1. 1.Center for Translational Medicine, School of PharmacyUniversity of MarylandBaltimoreUSA
  2. 2.University of ChicagoChicagoUSA
  3. 3.NorthShore University Health SystemEvanstonUSA
  4. 4.State Key Laboratory of Natural and Biomimetic Drugs (Peking University)BeijingChina
  5. 5.Alliance Statistics and Data CenterDuke UniversityDurhamUSA
  6. 6.Memorial Sloan Kettering Cancer CenterNew YorkUSA
  7. 7.Dana-Farber/Partners CancerCare/ Harvard Cancer CenterBostonUSA
  8. 8.Heartland Cancer Research NCORPSt. LouisUSA
  9. 9.Rutgers Cancer Institute of New JerseyNew BrunswickUSA
  10. 10.Mayo ClinicRochesterUSA
  11. 11.John H. Stroger Jr Hospital of Cook CountyChicagoUSA
  12. 12.Decatur Memorial Hospital/Cancer Care Specialists of Illinois/ Heartland Cancer Research NCORPDecaturUSA
  13. 13.University of California—San FranciscoSan FranciscoUSA
  14. 14.Center for Translational Medicine, School of PharmacyUniversity of MarylandBaltimoreUSA

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