Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model

Friberg, Lena E.; Sandström, Marie; Karlsson, Mats O.

doi:10.1007/s10637-009-9308-7

Cited by 41 publications

(61 citation statements)

References 36 publications

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“…frequency of dosing or infusion time) can lead to very distinct neutrophil dynamics and incidence of neutropenia [22], [27], [34], [36], [39]–[42]. Therefore, we used the Friberg model of neutropenia to study in detail how drug plasma time course correlated with incidence or severity by employing previously published semi-mechanistic population PK-PD models (Figure 1a) built from clinical ANC profiles following treatment with docetaxel [26], [34].…”

Section: Resultsmentioning

confidence: 99%

Dose Schedule Optimization and the Pharmacokinetic Driver of Neutropenia

et al. 2014

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Toxicity often limits the utility of oncology drugs, and optimization of dose schedule represents one option for mitigation of this toxicity. Here we explore the schedule-dependency of neutropenia, a common dose-limiting toxicity. To this end, we analyze previously published mathematical models of neutropenia to identify a pharmacokinetic (PK) predictor of the neutrophil nadir, and confirm this PK predictor in an in vivo experimental system. Specifically, we find total AUC and Cmax are poor predictors of the neutrophil nadir, while a PK measure based on the moving average of the drug concentration correlates highly with neutropenia. Further, we confirm this PK parameter for its ability to predict neutropenia in vivo following treatment with different doses and schedules. This work represents an attempt at mechanistically deriving a fundamental understanding of the underlying pharmacokinetic drivers of neutropenia, and provides insights that can be leveraged in a translational setting during schedule selection.

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Section: Resultsmentioning

confidence: 99%

Dose Schedule Optimization and the Pharmacokinetic Driver of Neutropenia

et al. 2014

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“…The most used and accepted model was developed by Friberg et al (2002), hereafter the reference model, which has demonstrated consistency among a wide variety of anticancer agents (Latz et al, 2006;Fetterly et al, 2008;Soto et al, 2010b) and has been used to describe neutropenic effects after drug combinations (Sandstrom et al, 2005;Soto et al, 2010a) and predict human hematologic toxicity from laboratory animal data (Friberg et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Semimechanistic Cell-Cycle Type–Based Pharmacokinetic/Pharmacodynamic Model of Chemotherapy-Induced Neutropenic Effects of Diflomotecan under Different Dosing Schedules

Mangas‐Sanjuán

Buil-Bruna

Garrido

et al. 2015

J Pharmacol Exp Ther

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The current work integrates cell-cycle dynamics occurring in the bone marrow compartment as a key element in the structure of a semimechanistic pharmacokinetic/pharmacodynamic model for neutropenic effects, aiming to describe, with the same set of system-and drug-related parameters, longitudinal data of neutropenia gathered after the administration of the anticancer drug diflomotecan (9,10-difluoro-homocamptothecin) under different dosing schedules to patients (n 5 111) with advanced solid tumors. To achieve such an objective, the general framework of the neutropenia models was expanded, including one additional physiologic process resembling cell cycle dynamics. The main assumptions of the proposed model are as follows: within the stem cell compartment, proliferative and quiescent cells coexist, and only cells in the proliferative condition are sensitive to drug effects and capable of following the maturation chain. Cell cycle dynamics were characterized by two new parameters, F Prol (the fraction of proliferative [Prol] cells that enters into the maturation chain) and k cycle (first-order rate constant governing cell cycle dynamics within the stem cell compartment). Both model parameters were identifiable as indicated by the results from a bootstrap analysis, and their estimates were supported by date from the literature. The estimates of F Prol and k cycle were 0.58 and 1.94 day 21, respectively. The new model could properly describe the neutropenic effects of diflomotecan after very different dosing scenarios, and can be used to explore the potential impact of dosing schedule dependencies on neutropenia prediction.

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“…Among these approaches, the model developed by Friberg et al [9] has been applied repeatedly to describe the time course of myelosuppression after administration of several cytotoxic anticancer drugs [12][13][14][15][16][17][18][19]. In addition, this model has successfully been applied in the scaling of the time course of myelosuppression from rat data to patients showing its usefulness in the drug development process [20].…”

Section: Introductionmentioning

confidence: 99%

Semi-mechanistic population pharmacokinetic/pharmacodynamic model for neutropenia following therapy with the Plk-1 inhibitor BI 2536 and its application in clinical development

Soto

Staab

Tillmann

et al. 2010

Cancer Chemother Pharmacol

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Purpose (1) To describe the neutropenic response of BI 2536 a polo-like kinase 1 inhibitor in patients with cancer using a semi-mechanistic model. (2) To explore by simulations (a) the neutropenic effects for the maximum tolerated dose (MTD) and the dose at which dose-limiting toxicity occurred, (b) the possibility to reduce the cycle duration without increasing neutropenia substantially, and (c) the impact of the initial absolute neutrophil count (ANC) on the degree of neutropenia for different doses. Experimental design BI 2536 was administered as intravenous infusion over 60 min in the dose range from 25 to 250 mg. Three different administration schedules were explored: (a) day 1, (b) days 1, 2, and 3 or (c) days 1 and 8 within a 3 week treatment cycle. BI 2536 plasma concentrations and ANC obtained during the first treatment cycle from 104 patients were analysed using the population approach with NONMEM VI. Results Neutropenia was described by a semi-mechanistic model resembling proliferation at the stem cell compartment, maturation, degradation, and homeostatic regulation. BI 2536 acts decreasing proliferation rate.Simulations showed that (1) all MTD doses showed an acceptable risk of neutropenia, (2) when BI 2536 is given as 200 mg single administration, cycle duration can be reduced from 3 to 2 weeks, and (3) baseline ANC might be considered to individualise the dose of BI 2536. Conclusions A semi-mechanistic population model was applied to describe the neutropenic effects of BI 2536. The model was used for simulations to support further clinical development.

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Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model

Cited by 41 publications

References 36 publications

Dose Schedule Optimization and the Pharmacokinetic Driver of Neutropenia

Dose Schedule Optimization and the Pharmacokinetic Driver of Neutropenia

Semimechanistic Cell-Cycle Type–Based Pharmacokinetic/Pharmacodynamic Model of Chemotherapy-Induced Neutropenic Effects of Diflomotecan under Different Dosing Schedules

Semi-mechanistic population pharmacokinetic/pharmacodynamic model for neutropenia following therapy with the Plk-1 inhibitor BI 2536 and its application in clinical development

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