Pharmacokinetic–pharmacodynamic modelling of neutrophil response to G‐CSF in healthy subjects and patients with chemotherapy‐induced neutropenia

Melhem, Murad; Delor, Isabelle; Pérez-Ruixo, Juan José; Harrold, John M.; Chow, Andrew; Wu, Lei; Jacqmin, Philippe

doi:10.1111/bcp.13504

Cited by 20 publications

(59 citation statements)

References 32 publications

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“…However, in our model, we utilized the input compartment (now termed marginated pool) as a reservoir for neutrophils to rapidly transition into circulation after G‐CSF dosing, similar to what was presented by Roskos et al ., and more recently by Ho et al . and Melhem et al . The marginated pool of granulocytes and neutrophils is a well‐established “compartment” that represents a reserve of neutrophils known to respond and demarginate rapidly into circulation with increased G‐CSF and other stimuli .…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…Since no G-CSF and peg-G-CSF concentrations were available, prior information about Melhem's model was used. 28 Moreover, because no PK data were collected in this study, individual chemotherapy concentrations were simulated based on previously published population PK (popPK) models of 5-FU, 31 our analysis, n was fixed to 3. 24,27,36,37 In this model, the effect of G-CSF depends on the concentration of free G-CSF or peg-G-CSF; therefore, the fraction of occupied…”

Section: Pk Model Developmentmentioning

confidence: 99%

“…Due to data sparseness, some PD parameters have been fixed according to literature values. 28 Only the following parameters were estimated: (Figure 2A), FOLFIRINOX regimen followed by G-CSF ( Figure 2B) or peg-G-CSF ( Figure 2C F I G U R E 4 Visual predictive checks of absolute neutrophil count for the final model based on 1000 simulations of study design on patients receiving daily granulocyte colony-stimulating factor after FOLFIRINOX regimen. Black dots represent the observed data.…”

Section: Final Poppk/pd Modelmentioning

confidence: 99%

See 1 more Smart Citation

Impact of granulocyte colony‐stimulating factor on FOLFIRINOX‐induced neutropenia prevention: A population pharmacokinetic/pharmacodynamic approach

Macaire

Paris

Vincent

et al. 2020

Brit J Clinical Pharma

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Granulocyte colony-stimulating factor (G-CSF) is frequently prescribed to prevent chemotherapy-induced neutropenia, but the administration schedule remains empirical in case of bimonthly chemotherapy such as FOLFIRINOX regimen. This pharmacokinetic/pharmacodynamic (PK/PD) study was performed to determine the effect of different G-CSF regimens on the incidence and duration of neutropenia following FOLFIRINOX administration in order to propose an optimal G-CSF dosing schedule. Methods: A population PK/PD model was developed to describe individual neutrophil time course from absolute neutrophil counts (ANC) obtained in 40 advanced cancer patients receiving FOLFIRINOX regimen. The structural model considered ANC dynamics, neutropenic effect of cytotoxics and the stimulating effect of G-CSF on neutrophils. Final model estimates were used to simulate different G-CSF dosing schedules for 1000 virtual subjects. The incidence and duration of neutropenia were then calculated for different G-CSF dosing schedules. Results: The final model successfully described the myelosuppressive effect induced by the 3 cytotoxics for all patients. Simulations showed that pegfilgrastim administration reduced the risk of severe neutropenia by 22.9% for subjects with low ANC at the start of chemotherapy. Median duration in this group was also shortened by 3.1 days when compared to absence of G-CSF. Delayed G-CSF administration was responsible for higher incidence and longer duration of neutropenia compared to absence of administration. Conclusion: The PK/PD model well described our population's ANC data. Simulations showed that pegylated-G-CSF administration 24 hours after the end of chemotherapy seems to be the optimal schedule to reduce FOLFIRINOX-induced neutropenia. We also underline the potential negative effect of G-CSF maladministration.

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“…The interaction of time with the G-CSF administration had a positive association, indicating that, while time increases, the medication's effect is more significant due to the effect reaches its maximum some days after the first dose. 23,24 Besides, the negative association between hospitals and G-CSF administration may be explained because, at HCUCH, G-CSF was used at the beginning of the neutropenia period, whereas at FALP, toward the end of the period; hence, it was more common to have lower levels of ANC during medication administration at HCUCH than at FALP. 25 Multilevel modeling allows us to work with correlated data and meets the assumption of linear regression, generating a proper way to obtain more reliable results.…”

Section: Dovepressmentioning

confidence: 99%

<p>IL-6 −572C>G and CARD8 304T>A Genetic Polymorphisms are Associated with the Absolute Neutrophil Count in Patients with Hematological Malignancies Under Chemotherapy: An Application of Multilevel Models to a Preliminary Pharmacogenetic Study</p>

Martínez

Alveal

Soto

et al. 2020

PGPM

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Purpose: Neutropenia is a common event in patients undergoing cytotoxic chemotherapy for the treatment of a hematological malignancy. Some polymorphisms, as IL-6 −572C>G (rs1800796), IL-1β −31 G>A (rs1143627), and CARD8 304T>A (rs2043211), in genes related to the inflammatory process, could affect the level of absolute neutrophil count (ANC) after chemotherapy. Since an efficient inflammatory process enhances neutrophil survival, we hypothesize that these polymorphisms are associated with ANC. Patients and Methods: We carried out a prospective cohort study in two hospitals in Santiago, Chile. The patients included were adults diagnosed with acute myeloblastic leukemia, acute lymphoblastic leukemia, or non-Hodgkin's lymphoma, undergoing cytotoxic chemotherapy. We use a multilevel linear regression model to test our hypothesis. The best model was selected using the Akaike's information criterion (AIC). Results: We analyzed 1726 hemograms and ANCs from 172 hospitalizations from 32 patients. The results show that CC and CG genotypes of IL-6 −572 C>G polymorphism are associated with higher ANCs compared with the GG genotype (Ln (ANC) ~ 0.81 IC95% 0.02-1.55). Similarly, TT and AT genotypes of CARD8 304T>A polymorphism were related to higher ANCs compared with AA (Ln (ANC) ~ 0.95 IC95% 0.02-1.82). IL-1β genetic polymorphism had no statistically significant association with ANC. Conclusion: IL-6 rs1800796 −572C>G and CARD8 rs2043211 304T>A polymorphisms are associated with the absolute neutrophil count in patients undergoing cytotoxic chemotherapy for treatment of hematological malignancies. Our findings might be useful to improve the safety of chemotherapy through predictive ANC models.

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Pharmacokinetic–pharmacodynamic modelling of neutrophil response to G‐CSF in healthy subjects and patients with chemotherapy‐induced neutropenia

Abstract: This qualified model simulates the time course of ANC in the absence or presence of chemotherapy and predicts nadir, time to nadir and time of recovery from different grades of neutropenia upon treatment with filgrastim and pegfilgrastim.

Cited by 20 publications

References 32 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

Impact of granulocyte colony‐stimulating factor on FOLFIRINOX‐induced neutropenia prevention: A population pharmacokinetic/pharmacodynamic approach

<p>IL-6 −572C>G and CARD8 304T>A Genetic Polymorphisms are Associated with the Absolute Neutrophil Count in Patients with Hematological Malignancies Under Chemotherapy: An Application of Multilevel Models to a Preliminary Pharmacogenetic Study</p>

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