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Pharmacokinetics and Pharmacodynamics of Melphalan in Multiple Myeloma Patients to Predict Clinical Adverse Outcomes PDF
By:Yu Kyoung Cho
Published on 2016 by

High dose melphalan (HDM) is part of the conditioning regimen in multiple myeloma (MM) patients 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. As a rescue regimen to manage neutropenia, 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 (PK) and pharmacodynamic (PD) model capable of predicting melphalan exposure and neutrophil kinetics in individual MM patients undergoing ASCT with high dose melphalan and G-CSF administration. In clinical PK studies, the choice of time points for collection of blood samples and the number of samples collected are important considerations for PK study design and may significantly impact the utility and versatility of the PK data generated from a clinical study. The original PK sampling scheme in our clinical trial comprised 8 specific time points and was aimed at producing robust data for subsequent PK/PD modeling. From the initial PK data in 28 patients, modeling and simulation suggested we could reduce sampling to include only 6 time points without significantly sacrificing precision in PK parameter estimation. The remaining patients in this study then received only 6 blood draws, and a retrospective evaluation of sampling schemes was conducted using data from a total 119 patients (47 with 8 time points, and 72 with 6 time points). The comparison of different last sampling points demonstrated that the inclusion of at least one sampling point after 180 minutes beyond the end of infusion is required to avoid sacrificing PK parameter precision, and all models with less than 7 points revealed a large shift in parameter estimates compared to the original model with 8 sampling time points. This suggests that sampling schemes with a minimum of 7 specimens is required for maximizing accuracy and precision in melphalan PK parameters. Thereafter, we built the final population PK model incorporating significant covariates. Fat free mass, hematocrit, creatinine clearance, and SLC7A5 polymorphism were chosen for the final covariate model that explained inter-patient variability of melphalan PK. We also investigated the influence of G-CSF schedules on neutrophils and clinical outcomes after HDM followed by ASCT regimen. The duration of severe neutropenia was significantly increased for patients receiving G-CSF on day +7 compared to those receiving it on day +1, and there is a trend for risk of relapse for patients receiving G-CSF on day +1 estimated to be half of that of those receiving G-CSF on day +7. Consequently, the impact of G-CSF schedules on neutrophils was incorporated in the PK/PD model. The extended melphalan PK/PD model incorporated several covariates, including G-CSF, ANC, hematocrit, race, sex, and BUN. The resulting model explained significant portions of inter-individual 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.

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Download Pharmacokinetics and Pharmacodynamics of Melphalan in Multiple Myeloma Patients to Predict Clinical Adverse Outcomes PDF Free

Download Pharmacokinetics and Pharmacodynamics of Melphalan in Multiple Myeloma Patients to Predict Clinical Adverse Outcomes Books Free

Download Pharmacokinetics and Pharmacodynamics of Melphalan in Multiple Myeloma Patients to Predict Clinical Adverse Outcomes Free

Download Pharmacokinetics and Pharmacodynamics of Melphalan in Multiple Myeloma Patients to Predict Clinical Adverse Outcomes PDF

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