Population pharmacokinetics of high-dose etoposide in children receiving different conditioning regimens

Würthwein, Gudrun; Klingebiel, Thomas; Krümpelmann, Sebastian; Metz, Melanie; Schwenker, Kerstin; Kranz, Karen; Lanvers, Claudia; Boos, Joachim

doi:10.1097/00001813-200201000-00012

Cited by 18 publications

(13 citation statements)

References 25 publications

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“…For high-dose cyclophosphamide treatment (1,850-7,000 mg/m 2 ), the maximum reported serum concentration (Cmax) was 2.664 mg/mL [24,25]. For high-dose etoposide treatment (1,480-1,665 mg/m 2 ), the reported Cmax was 0.1 mg/mL [26,27]. Based on this information, the CC10 was selected as the drug concentration for further experiments.…”

Section: Etoposide Increases Il-8 Secretion From Bmscs and Causes Lonmentioning

confidence: 99%

Etoposide-mediated interleukin-8 secretion from bone marrow stromal cells induces hematopoietic stem cell mobilization

Kang

Lee²,

Kim³

et al. 2020

Preprint

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Abstract Background This study assessed the mechanism of hematopoietic stem cell (HSC) mobilization using etoposide with granulocyte-colony stimulating factor (G-CSF) and determined how it differed from that using cyclophosphamide with G-CSF or G-CSF alone.Methods The study analyzed data from 173 non-Hodgkin’s lymphoma patients who underwent autologous peripheral blood stem cell transplantation (auto-PBSCT), in vitro experiments using HSCs and bone marrow stromal cells (BMSCs), and in vivo mouse model studies.Results The etoposide with G-CSF mobilization group showed the highest yield of CD34+ cells and the lowest change in white blood cell counts during mobilization. Etoposide triggered interleukin (IL)-8 secretion from BMSCs and caused long-term BMSC toxicity, which were not observed with cyclophosphamide treatment. The expansion of CD34+ cells cultured in BMSC-conditioned medium containing IL-8 was more remarkable than that without IL-8. The expression of CXCR2, mTOR, and cMYC in HSCs was gradually enhanced at 1, 6, and 24 h after IL-8 stimulation. In animal studies, the etoposide with G-CSF mobilization group presented stronger expression of IL-8-related cytokines and MMP9 and scantier expression of SDF-1 in the bone marrow, compared to the other groups not treated with etoposide.Conclusion Collectively, the unique mechanism of etoposide with G-CSF-mediated mobilization is associated with the secretion of IL-8 from BMSCs, causing the enhanced proliferation and mobilization of HSCs in the bone marrow, which was not observed in the mobilization using cyclophosphamide with G-CSF or G-CSF alone. Moreover, the long-term toxicity of etoposide to BMSC emphasizes the need for further studies to develop more efficient and safe chemo-mobilization strategies.

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Section: Etoposide Increases Il-8 Secretion From Bmscs and Causes Lonmentioning

confidence: 99%

Etoposide-mediated interleukin-8 secretion from bone marrow stromal cells induces hematopoietic stem cell mobilization

Kang

Lee²,

Kim³

et al. 2020

Preprint

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“…There are many studies describing VP‐16 PK, although there are still only a few concerning children who underwent HSCT and received high‐dose VP‐16 as a conditioning regimen (9, 10). Concurrently, there is no study referring to children with ALL conditioned with FTBI and VP‐16 at a single dose of 60 mg/kg, which nowadays is one of the major regimens used in children with ALL, the most common indication for allo‐HSCT.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of high‐dose etoposide administered in combination with fractionated total‐body irradiation as conditioning for allogeneic hematopoietic stem cell transplantation in children with acute lymphoblastic leukemia

Chrzanowska¹,

Sobiak²,

Grund³

et al. 2010

Pediatric Transplantation

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Etoposide (VP-16) is one of the most widely used antitumor agents in pediatric oncology as well as chemotherapeutic agents used in conditioning regimen prior to allo-HSCT for childhood ALL. This study included 21 children with ALL who underwent allo-HSCT after conditioning with FTBI and high-dose of VP-16 (60 mg/kg) given intravenously as single four-h infusion on day -3 (n=2) or day -4 (n=19) prior to allo-HSCT. Blood samples were collected at defined time intervals until 120 h elapsed from the end of infusion. VP-16 plasma concentrations were determined using validated HPLC method. Three-compartment model was assumed for assessing PK parameters of VP-16. The median value of VP-16 C(max) measured at the end of infusion was 188.0 μg/mL (range 148.0-407.0 μg/mL). Out of 21 studied children, VP-16 was still detectable in 17 patients 72 h (median concentration 0.31 μg/mL) and in eight patients 96 h (median concentration 0.31 μg/mL) after the end of infusion. VP-16 concentration 96 h after the end of infusion was positively correlated with VP-16 AUC and negatively correlated with VP-16 CL normalized to body weight.

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“…A clearance of etoposide at a range lower than that reported in the literature was described in children who underwent treatment with high-dose etoposide. 20 As regard actinomycin D, a study performed in a pediatric population reported a higher median exposure in children whose body weight was <40 kg. 21 A possible role of age in the pharmacokinetics of doxorubicin is not well defined.…”

Section: Discussionmentioning

confidence: 99%

Predictive Factors of Histologic Response to Primary Chemotherapy in Patients With Ewing Sarcoma

Ferrari

Bertoni²,

Palmerini

et al. 2007

Journal of Pediatric Hematology/Oncology

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A correlation between chemotherapy-induced necrosis and prognosis has been reported in Ewing sarcoma. To identify factors influencing histologic response data from 122 patients with Ewing sarcoma surgically treated were reviewed. Primary chemotherapy was based on vincristine, doxorubicin, cyclophosphamide, ifosfamide, actinomycin-D, and etoposide. Patients with complete necrosis or only scattered foci of viable tumor cells were good responders (GRs), the remaining patients poor responders (PRs). Age, sex, site and size of the tumor, fever at diagnosis, and lactate dehydrogenase level were clinical variables investigated. Mean age was 13.3+/-6 in GR and 18.1+/-9 in PR (P<0.0005); GR rate was 71% in patients18 years (P=0.003). Female were more likely to achieve a GR (F 64% vs. M 42%, P<0.02). After multivariate analysis sex and age retained statistical significance. Age and sex influence the histologic response in patients with Ewing sarcoma.

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Population pharmacokinetics of high-dose etoposide in children receiving different conditioning regimens

Cited by 18 publications

References 25 publications

Etoposide-mediated interleukin-8 secretion from bone marrow stromal cells induces hematopoietic stem cell mobilization

Etoposide-mediated interleukin-8 secretion from bone marrow stromal cells induces hematopoietic stem cell mobilization

Pharmacokinetics of high‐dose etoposide administered in combination with fractionated total‐body irradiation as conditioning for allogeneic hematopoietic stem cell transplantation in children with acute lymphoblastic leukemia

Predictive Factors of Histologic Response to Primary Chemotherapy in Patients With Ewing Sarcoma

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