Pharmacodynamic Modeling of the Entire Time Course of Leukopenia after a 3‐Hour Infusion of Paclitaxel

Abstract

The entire time course of leukopenia after anticancer treatment is clinically more relevant than a singly measured nadir count. In order to identify factors associated with neutropenic fever, a mechanistic pharmacodynamic model with two compartments corresponding to leukocytes in bone marrow and peripheral blood was applied to describe the time course of leukopenia. Key words: Pharmacokinetics -Pharmacodynamics -Leukopenia -Fever -ChemotherapyLeukopenia is the primary toxicity of many anticancer agents and precludes dose escalation or scheduled administration of repeated cycles. Most pharmacodynamic analyses of anticancer agents focus on this toxicity, and a singly measured nadir leukocyte count or the surviving fraction of leukocytes at the nadir (nadir count divided by the pretreatment count) is modeled.1-4) However, leukopenia changes continuously with time after treatment, and the singly measured nadir count is not the best predictor of clinically relevant events, including fever or toxic death, considering that patients with prolonged leukopenia have a greater risk of infection than patients with more rapid recovery.5) The time period during which the leukocyte count remains below a certain level (i.e., 1000 or 2000/µl, Fig. 1a) or the area between the curve of time versus leukocyte counts and the line of a specific leukocyte count (Fig. 1b) may be clinically more important than the singly measured nadir count (Fig. 1c). Not only the magnitude of leukopenia, but also the time course of leukopenia should be considered in pharmacodynamic analysis of anticancer agents.In most of the conventional pharmacodynamic analyses, information on plasma concentrations of the drug, which change with time, is summarized by a time-independent parameter such as the area under the time-concentration curve (AUC), the peak concentration, or the time above a threshold concentration. 2,[6][7][8][9][10] The relationship between one of these summary parameters (e.g., AUC) and the nadir count, which is also a summary parameter of pharmacodynamics, is evaluated by using a model. In this case, patients with the same AUC but a different time course of plasma concentrations would have the same nadir value, although they have a different time course of leukopenia. It is useful to consider the time course of the drug concentration when the time course of leukopenia after treatment with an anticancer drug is modeled. Although pharmacodynamic models for the time course of leukopenia have been reported, they were mathematical and ignored the time course of the drug concentration. 11-14)Recently we developed a model to describe the entire time course of leukopenia after treatment with anticancer agents by using the time course of plasma concentrations as input into the model. 15) By using the model, the time that leukocyte counts remain below a certain value or the area between the time course of leukopenia and the line of a specific leukocyte count can be estimated. In this study, we have applied the pharmacodynamic model to the time course ...

Irinotecan pharmacokinetics-pharmacodynamics: the clinical relevance of prolonged exposure to SN-38

“…In our current study, a rich data set was available with haematological toxicity data, which might explain the moderate predictive performance of the PK/PD relationship using (assumed) nadir counts. Clinically even more important PD parameters than the just mentioned parameters may be (i) the time period during which the neutrophil count remains below a certain level (for instance 4610 9 cells l 71 ) or (ii) the area between the curve of time vs leukocyte count and the line representing a cell count of 4610 9 cells l 71 (Minami et al, 2001). Also in our current study, this area was shown to demonstrate the best correlation of all tested PK/PD combinations.…”

“…Also in our current study, this area was shown to demonstrate the best correlation of all tested PK/PD combinations. In order to further optimise PK/PD relationships, a population model for CPT-11-induced neutropenia by modelling the full time course of haematological toxicity is currently being developed, as done previously for paclitaxel and etoposide (Karlsson et al, 1998;Minami et al, 1998Minami et al, , 2001.…”

Pharmacodynamic modeling of chemotherapeutic effects: Application of a transit compartment model to characterize methotrexate effects in vitro

“…Two cancer cell lines, Ehrlich ascites cells and sarcoma 180 cells, were exposed for 24 hours to MTX concentrations that varied more than 700-fold (0.19-140 g/mL). Viable cells were counted on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 20, 22, and 24 for Ehrlich ascites cells and on days 1,2,3,5,7,9,11,13,14,15,17,19, and 21 for sarcoma 180 cells, through the use of a tetrazolium assay. Although MTX was removed 24 hours after application, cell numbers reached nadir values more than 100 hours after MTX exposure.…”

“…[6][7][8] In lieu of time-course models, PKPD individualization efforts have largely attempted to relate a time-averaged value of drug exposure (eg, the area under the plasma concentration-time curve) to peak effect or peak toxicity (eg, nadir white blood cell count). [9][10][11][12][13] Unfortunately, such "static" approaches are of limited value, as these models do not predict the time course of effect and, thus, may not be used to predict optimal schedules of drug administration.…”

Paclitaxel Against Cancer: A Short Review

“…Paclitaxel in various studies is showed as effective anticancer agent against lung, breast, ovarian, leukopenia and liver cancer [24][25][26][27][28][29]. It is also known to produce macrophage IL-12 in tumor bearing hosts which down regulates the tumor growth significantly by selective dysregulation of IL-12 p40 expression [30].…”