Pharmacokinetic-Pharmacodynamic Model of Neutropenia in Patients With Myeloma Receiving High-Dose Melphalan for Autologous Stem Cell Transplant

• Type of Material: Article
• Authors: Yu Kyoung Cho, Ohio State University; Donald J. Irby, Ohio State University; Junan Li, Ohio State University; Douglas W. Sborov, Ohio State University; Diane R. Mould, Projections Research Inc.; Mohamed Badawi, Ohio State University; Anees Dauki, Ohio State University; Misty Lamprecht, Ohio State University; Ashley E. Rosko, Ohio State University; Soledad Fernandez, Ohio State University; Erinn M. Hade, Ohio State University; Craig Hofmeister, Emory University; Ming Poi, Ohio State University; Mitch A. Phelps, Ohio State University
• Language: English
• Date: 2018-11-01
• Publisher: Wiley Open Access: Various Creative Commons Licenses
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/psp4.12345
• Title of Journal or Parent Work: CPT: Pharmacometrics and Systems Pharmacology
• ISSN: 2163-8306
• Volume: 7
• Issue: 11
• Start Page: 748
• End Page: 758
• Grant/Funding Information: This research was supported by Multiple Myeloma Opportunities for Research and Education (MMORE), a Pelotonia IDEA award (46050‐502048), the Ohio State University Comprehensive Cancer Center Core Grant (P30 CA016058), and an Eli‐Lilly fellowship.
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Oncology

Abstract

High-dose melphalan (HDM) is part of the conditioning regimen in patients with multiple myeloma (MM) receiving autologous stem cell transplantation (ASCT). However, individual sensitivity to melphalan varies, and many patients experience severe toxicities. Prolonged severe neutropenia is one of the most severe toxicities and contributes to potentially life-threatening infections and failure of ASCT. Granulocyte-colony stimulating factor (G-CSF) is given to stimulate neutrophil proliferation after melphalan administration. The aim of this study was to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model capable of predicting neutrophil kinetics in individual patients with MM undergoing ASCT with high-dose melphalan and G-CSF administration. The extended PK/PD model incorporated several covariates, including G-CSF regimen, stem cell dose, hematocrit, sex, creatinine clearance, p53 fold change, and race. The resulting model explained portions of interindividual variability in melphalan exposure, therapeutic effect, and feedback regulation of G-CSF on neutrophils, thus enabling simulation of various doses and prediction of neutropenia duration.