Characterization of Endogenous G-CSF and the Inverse Correlation to Chemotherapy-Induced Neutropenia in Patients with Breast Cancer Using Population Modeling

Quartino, Angelica; Karlsson, Mats O.; Lindman, Henrik; Friberg, Lena E.

doi:10.1007/s11095-014-1429-9

Cited by 53 publications

(81 citation statements)

References 46 publications

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“…Several variations of the compartmental neutropenia model previously proposed by Friberg et al . were evaluated, including those that incorporated direct G‐CSF effect on neutrophil proliferation and maturation . The final neutropenia model, depicted in Figure , comprised PD parameters to describe proliferation of cells, delayed PD effect through transition to the observed neutrophils, elimination of circulating neutrophils, and feedback from circulating neutrophils to proliferation rate constant (k prol ).…”

Section: Methodsmentioning

confidence: 99%

“…The k prol was assumed equal to the transition rate constant between transit compartments (k tr ), which was defined as 4/mean transit time (MTT) in this three‐compartment transit model, where MTT is the mean transit time of neutrophils. The elimination rate constant of neutrophils ( k circ ), in which

K_{normalcirc} = \frac{ln (2)}{neutrophils half‐life}

was fixed by the reported neutrophil half‐life of 7 hours . The feedback mechanism was described by (Circ 0 /Circ) γ , the ratio between estimated baseline ANC (Circ 0 or BASE) and circulating ANC (Circ) at a given time with γ parameter by G‐CSF regulation.…”

Section: Methodsmentioning

confidence: 99%

“…is well established and has been applied to various chemotherapeutic agents. Furthermore, several approaches have been proposed to incorporate the impact on neutropenia from G‐CSF after primary chemotherapy . However, these approaches have not yet been evaluated in HDM/ASCT.…”

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confidence: 99%

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Pharmacokinetic‐Pharmacodynamic Model of Neutropenia in Patients With Myeloma Receiving High‐Dose Melphalan for Autologous Stem Cell Transplant

Cho

Irby

Sborov

et al. 2018

CPT Pharmacom & Syst Pharma

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High‐dose melphalan (HDM) is part of the conditioning regimen in patients with multiple myeloma (MM) 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. 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/pharmacodynamic (PK/PD) model capable of predicting neutrophil kinetics in individual patients with MM undergoing ASCT with high‐dose melphalan and G‐CSF administration. The extended PK/PD model incorporated several covariates, including G‐CSF regimen, stem cell dose, hematocrit, sex, creatinine clearance, p53 fold change, and race. The resulting model explained portions of interindividual 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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Section: Methodsmentioning

confidence: 99%

K_{normalcirc} = \frac{ln (2)}{neutrophils half‐life}

Section: Methodsmentioning

confidence: 99%

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Pharmacokinetic‐Pharmacodynamic Model of Neutropenia in Patients With Myeloma Receiving High‐Dose Melphalan for Autologous Stem Cell Transplant

Cho

Irby

Sborov

et al. 2018

CPT Pharmacom & Syst Pharma

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show abstract

“…However, this mechanism can be identified only if the endogenous hormone data are available together with the circulating cell counts. PK/PD models of chemotherapy induced neutropenia have been developed where the negative feedback is replaced by a receptor mediated disposition models of endogenous G-CSF [35,36]. We applied the same concept to account for the negative feedback due to downregulation of megakaryocytes and platelets despite the absence of the rebound in the platelet count in our multi-cycle data.…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamic model for chemoradiotherapy-induced thrombocytopenia in mice

Krzyzanski

Pérez‐Ruixo

Harrold

2015

J Pharmacokinet Pharmacodyn

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A mechanistic model describing the effects of chemotherapy and radiation on platelet counts and endogenous thrombopoietin (eTPO) in mice was developed. Thrombocytopenia was induced in mice by injection of carboplatin followed by the whole body irradiation on days 0, 28, and 56, with platelet and eTPO samples collected over 84 days. The pharmacodynamic model consisted of a series of aging compartments representing proliferating megakaryocyte precursors, megakaryocytes, and platelets with possible eTPO clearance through internalization. The cytotoxic effects of treatment were described by the kinetics of the effect (K-PD) model, and stimulation of platelet production by eTPO was considered to be driven by receptor occupancy. The proposed PD model adequately described the platelet counts and eTPO concentrations in mice by accounting for nadirs and peaks of platelet count, and rebounds in eTPO time course profiles. The estimates of model parameters were in good agreement with their physiological values reported in literature for mice with platelet lifespan of 4.3 days and 185 cMpl receptors per platelet. The predicted duration of the treatment effect was 0.82 h (approximately 5 carboplatin half-lives in mice). The data was not informative about the eTPO stimulatory effect as the nominal precursor production rate was sufficient to account for platelet response to treatment. The model quantified the inverse relationship between eTPO levels and platelet counts and offered an explanation of the tolerance effect observed in the eTPO data. The simulated rebound in free receptors levels correlated with rebounds in eTPO levels. The model suggests that the duration of the toxic effects is determined by the turnover of the proliferating cells in the bone marrow. This indicates that the lifespan of the target cells (megakaryocyte precursors, megakaryocytes and platelets) is a key determinant in the duration of both drug exposure and toxicity due to treatment. The model can be extended to account for pharmacokinetics of exogenous drugs and be applied to analysis of human data.

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“…Stężenie G-CSF we krwi wykazuje ścisłą zależność od zawartości granulocytów i jest proporcjonalne do głębokości neutropenii. U chorych otrzymujących chemioterapię najwyższe stężenia G-CSF występują w okresie spadku neutropenii po chemioterapii [4].…”

Section: Wprowadzenieunclassified

Czynniki pobudzające granulopoezę są nadużywane w systemowym leczeniu onkologicznym

Walewski¹

2016

Nowotwory. Journal of Oncology

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Zastosowanie czynników stymulujących granulopoezę u chorych na nowotwory otrzymujących chemioterapię jest powszechne, a szereg wiarygodnych badań populacyjnych sugeruje, że międzynarodowe rekomendacje często nie są przestrzegane, a w konsekwencji czynniki wzrostu są nadużywane lub nie są stosowane według wskazań. Ponadto niektóre badania randomizowane podważają zasadność taktyki intensyfikacji chemioterapii możliwej dzięki zastosowaniu czynników wzrostu. Dokonano przeglądu i dyskusji piśmiennictwa opisującego okoliczności wskazujące na nadużywanie lub niewykorzystywanie G-CSF w praktyce onkologicznej. Overuse of granulocyte colony stimulating factors in systemic cancer therapyThe use of granulopoietic agents has become widespread in cancer patients receiving chemotherapy, and a number of reliable population-based studies suggest major deviations from the international evidence-based guidelines. In effect, the growth factors are overused or not used when clinically indicated. In addition, recent randomised studies in patients with aggressive lymphoma provide evidence against the benefit of once commonly believed tactics of dose-dense chemotherapy made possible by the use of G-CSF. We review of contributions implicating an overuse or underuse of G-CSF in oncology practice.

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Characterization of Endogenous G-CSF and the Inverse Correlation to Chemotherapy-Induced Neutropenia in Patients with Breast Cancer Using Population Modeling

Cited by 53 publications

References 46 publications

Pharmacokinetic‐Pharmacodynamic Model of Neutropenia in Patients With Myeloma Receiving High‐Dose Melphalan for Autologous Stem Cell Transplant

Pharmacokinetic‐Pharmacodynamic Model of Neutropenia in Patients With Myeloma Receiving High‐Dose Melphalan for Autologous Stem Cell Transplant

Pharmacodynamic model for chemoradiotherapy-induced thrombocytopenia in mice

Czynniki pobudzające granulopoezę są nadużywane w systemowym leczeniu onkologicznym

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