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Model-Based Approach to Describe G-CSF Effects in Carboplatin-Treated Cancer Patients

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ABSTRACT

Purpose

Granulocyte colony-stimulating factor (G-CSF) is often used in cancer patients receiving cytotoxic drugs to prevent or reduce high grade neutropenia. We propose a pharmacokinetic/pharmacodynamic model to describe myelotoxicity in both G-CSF treated and non-treated patients that shall increase our understanding of G-CSF effects.

Methods

The model was built from absolute neutrophil counts (ANC) obtained in 375 carboplatin-treated patients, 47 of whom received G-CSF. It includes some prior information on G-CSF taken from the literature. Simulations were performed to understand differences in G-CSF effects and explore the impact of G-CSF formulation.

Results

Our model well described the data in all patients. Model simulations showed that G-CSF was not as beneficial as expected in some patients. Furthermore, a longer and stronger effect was observed for the pegylated formulation in comparison with the daily standard formulation even if the latter was given for 11 consecutive days.

Conclusions

The proposed model allows a mechanistic interpretation of G-CSF effects on ANC and raises the question of a systematic beneficial effect of G-CSF treatment. Other studies are needed to confirm these findings and help identifying patients for whom G-CSF is beneficial.

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Abbreviations

Abs 1 :

Absorption compartment for filgrastim/lenograstim

Abs 2 :

Absorption compartment for pegfilgrastim

ANC :

Absolute neutrophil count

Base :

Baseline level of absolute neutrophil count

C carbo :

Ultrafiltrable circulating (plasma) concentration of carboplatin

C u :

Free circulating concentration controlling G-CSF effects on bone marrow, calculated as the sum of non-pegylated and pegylated G-CSF free circulating (serum) concentrations

Circ :

Circulating mature neutrophil count (=ANC)

E max 1 :

Maximal effect of non-pegylated or pegylated G-CSF on proliferation

E max 2 :

Maximal effect of non-pegylated or pegylated G-CSF on maturation

EC 50 1 :

Value of Cu eliciting 50% of the maximal effect on proliferation

EC 50 2 :

Value of Cu eliciting 50% of the maximal effect on maturation

F1(F2) :

Absolute bioavailability of filgrastim/lenograstim(pegfilgrastim) after subcutaneous administration (which, in the model, is taking into account via the apparent volume of distribution)

G-CSF :

Granulocyte colony-stimulating factor

k :

Transit rate constant between compartments of granulopoiesis (function of Cu) \( \left(k={k}_{tr}\times \left(1+\frac{E_{\max }2\times {C}_u}{E{C}_{50}2+{C}_u}\right)\right) \)

k a 1(2) :

Absorption rate constant for filgrastim/lenograstim(pegfilgrastim)

k circ :

Rate constant of elimination of neutrophils from the systemic blood circulation

K D :

Dissociation constant of RC complex ( = k off /k on )

k el 1 :

Rate constant for the linear, non-specific elimination of endogenous G-CSF and filgrastim/lenograstim

kel2:

Rate constant for the linear, non-specific elimination of pegfilgrastim

k GCSF :

Rate constant of endogenous G-CSF production

k int :

Rate constant for non-pegylated or pegylated G-CSF elimination after binding to receptors and internalization

k prol :

Proliferation rate constant

k tr :

“Virtual” transit rate constant when Cu = 0 (cf. k)

MTT :

Mean transit time for maturing precursors in bone marrow \( \left( MTT=4/{k}_{tr}\times \left(1+\frac{E_{\max }2\times {C}_u}{E{C}_{50}2+{C}_u}\right)\right) \)

PK :

Pharmacokinetic(s)

PK/PD :

Pharmacokinetic(s)/pharmacodynamic(s)

Prol :

Stem cell and progenitor cell count (i.e. proliferative cells) in bone marrow

R :

Concentration in G-CSF receptors present on circulating neutrophils

RC :

Concentration in bound G-CSF complex (pegylated and non-pegylated G-CSF)

R max :

Maximal amount of receptors involved in nonlinear, specific clearance of pegylated and on-pegylated G-CSF (=R + RC)

RSE :

Relative standard error

Slope :

Sensitivity to carboplatin myelotoxicity

Transit 1,2,3 :

Maturating granulocyte precursor count in transit compartments 1, 2 and 3, respectively

VD a 1(2) :

Apparent volume of distribution of G-CSF (pegylated G-CSF) after subcutaneous administration of filgrastim/lenograstim (pegfilgrastim) (VD1(2)/F1(2))

ξ :

Proportionality constant for the amount of G-CSF receptors per cell

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Authors and Affiliations

  1. Unité de Médecine, Urgences Soins Intensifs, Université de Toulouse, INP, Ecole Nationale Vétérinaire de Toulouse, 31076, Toulouse, France

    Mélanie L. Pastor

  2. INRA/ENVT, UMR1331, Toxalim, 31027, Toulouse, France

    Mélanie L. Pastor, Céline M. Laffont & Didier Concordet

  3. Institut Claudius-Regaud, Université de Toulouse, EA4553 20 rue du Pont-Saint-Pierre, 31052, Toulouse, France

    Laurence Gladieff & Etienne Chatelut

  4. UFR Sciences Pharmaceutiques et Biologiques, Université de Bourgogne, 7 Bd Jeanne d’Arc, Dijon, 21079, France

    Antonin Schmitt

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  1. Mélanie L. Pastor
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  2. Céline M. Laffont
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Correspondence to Mélanie L. Pastor.

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Pastor, M.L., Laffont, C.M., Gladieff, L. et al. Model-Based Approach to Describe G-CSF Effects in Carboplatin-Treated Cancer Patients. Pharm Res 30, 2795–2807 (2013). https://doi.org/10.1007/s11095-013-1099-z

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  • DOI: https://doi.org/10.1007/s11095-013-1099-z

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