A simultaneous analysis of the time course of leukocytes and neutrophils following docetaxel administration using a semi-mechanistic model
Quartino, Angelica L., Lena E. Friberg, Mats O. Karlsson
Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy, Uppsala University, Sweden
Objectives: The previously developed semi-mechanistic pharmacokinetic-pharmacodynamic model for the time course of docetaxel induced myelosuppression [1] was applied separately to measurements of total leukocyte counts and neutrophil counts. As neutrophils are a part of the leukocytes (60-70%), a combined analysis may have advantages. The aim of this study was to model the time course of leukocytes and neutrophils simultaneously. A simultaneous fit of the data may enable prediction of neutropenia when only leukocytes are measured and allow comparisons between neutrophils and non-neutrophils with respect to system related parameters and drug effect.
Methods: The analysis included 637 patients who were treated with a one hour infusion of 75 or 100 mg/m2 docetaxel. Individual concentration time profiles were created using a population pharmacokinetic model [2]. A total of 3549 pairwise observations of leukocytes and neutrophils were analyzed. The modeling was done using NONMEM (ver VIβ) using the FOCE method with interaction.
Results: The developed simultaneous model consisted of a neutrophil and a non-neutrophil model, each with the same structure as previously described [1], but allowing different parameter values. The observed leukocyte count was modeled to be the sum of the predicted neutrophils and non-neutrophils. Separate residual errors for neutrophils and non-neutrophils were applied in combination with a L2-data item that forces the residual error for neutrophils to be the same for the observation of neutrophils and leukocytes at the same time point. Box-Cox transforming the data with a factor of 0.2 improved model stability and goodness of fit plots.
Separating the half-life of the circulating cells from the mean transit time (MTT) for cell maturation and fixing it to 7 hours (literature value for neutrophils) resulted in an increase of MTT and of the parameter describing the drug-effect, slope, for both cell types. The parameters for neutrophils were correlated with their corresponding parameters for non-neutrophils (46-68%). For both neutrophils and non-neutrophils the MTT and slope were correlated (38-42%).
Conclusion: A joint model describing the time course of both neutrophils and leukocytes following docetaxel treatment described the data well and illustrates the differences between the cell types; the neutrophils mature more slowly, have a weaker feedback mechanism and are more sensitive to docetaxel than non-neutrophils. The model can also predict neutrophil count from leukocyte measurements.
References
[1] Friberg, LE, Henningsson A, Maas H, Nguyen L, and
[2] Bruno R, Vivler N, Vergninol JC, et al: A population pharmacokinetic model for docetaxel (Taxotere): Model building and validation. J Pharmacokinetics Biopharm 1996, 24:153-172