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. Gobburu

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 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. Clinicaltrials.gov ID: NCT00785291

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalAAPS Journal
DOIs
StateAccepted/In press - Jun 15 2017

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Peripheral Nervous System Diseases
Paclitaxel
Leukemia
Breast Neoplasms
Drug Therapy
Neoplasms
130-nm albumin-bound paclitaxel
ixabepilone
Linear Models
Pharmaceutical Preparations
Physicians

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Kinetic-Pharmacodynamic Model of Chemotherapy-Induced Peripheral Neuropathy in Patients with Metastatic Breast Cancer Treated with Paclitaxel, Nab-Paclitaxel, or Ixabepilone : CALGB 40502 (Alliance). / Mehrotra, Shailly; Sharma, Manish R.; Gray, Elizabeth; Wu, Kehua; Barry, William T.; Hudis, Clifford; Winer, Eric P.; Lyss, Alan P.; Toppmeyer, Deborah L.; Moreno Aspitia, Alvaro; Lad, Thomas E.; Valasco, Mario; Overmoyer, Beth; Rugo, Hope; Ratain, Mark J.; Gobburu, Jogarao V.

In: AAPS Journal, 15.06.2017, p. 1-13.

Research output: Contribution to journalArticle

Mehrotra, S, Sharma, MR, Gray, E, Wu, K, Barry, WT, Hudis, C, Winer, EP, Lyss, AP, Toppmeyer, DL, Moreno Aspitia, A, Lad, TE, Valasco, M, Overmoyer, B, Rugo, H, Ratain, MJ & Gobburu, JV 2017, 'Kinetic-Pharmacodynamic Model of Chemotherapy-Induced Peripheral Neuropathy in Patients with Metastatic Breast Cancer Treated with Paclitaxel, Nab-Paclitaxel, or Ixabepilone: CALGB 40502 (Alliance)', AAPS Journal, pp. 1-13. https://doi.org/10.1208/s12248-017-0101-9
Mehrotra, Shailly ; Sharma, Manish R. ; Gray, Elizabeth ; Wu, Kehua ; Barry, William T. ; Hudis, Clifford ; Winer, Eric P. ; Lyss, Alan P. ; Toppmeyer, Deborah L. ; Moreno Aspitia, Alvaro ; Lad, Thomas E. ; Valasco, Mario ; Overmoyer, Beth ; Rugo, Hope ; Ratain, Mark J. ; Gobburu, Jogarao V. / Kinetic-Pharmacodynamic Model of Chemotherapy-Induced Peripheral Neuropathy in Patients with Metastatic Breast Cancer Treated with Paclitaxel, Nab-Paclitaxel, or Ixabepilone : CALGB 40502 (Alliance). In: AAPS Journal. 2017 ; pp. 1-13.
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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 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. Clinicaltrials.gov ID: NCT00785291",
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AU - Mehrotra, Shailly

AU - Sharma, Manish R.

AU - Gray, Elizabeth

AU - Wu, Kehua

AU - Barry, William T.

AU - Hudis, Clifford

AU - Winer, Eric P.

AU - Lyss, Alan P.

AU - Toppmeyer, Deborah L.

AU - Moreno Aspitia, Alvaro

AU - Lad, Thomas E.

AU - Valasco, Mario

AU - Overmoyer, Beth

AU - Rugo, Hope

AU - Ratain, Mark J.

AU - Gobburu, Jogarao V.

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N2 - 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. Clinicaltrials.gov ID: NCT00785291

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