Pharmacokinetics of high-dose etoposide

Newman, Edward M.; Doroshow, James H.; Forman, Stephen J.; Blume, Karl G.

doi:10.1038/clpt.1988.73

Cited by 26 publications

(4 citation statements)

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“…Pharmacokinetics of etoposide have been reported to be dose-linear (Hande et al 1984;Newman et al 1988;Slevin 1991;Köhl et al 1992;Würthwein and Boos 2001). To date, however, the relationship between the pharmacokinetic parameters of etoposide and drug dose has been compiled by comparing the data generated from different patient groups who were treated with different dose levels.…”

Section: Discussionmentioning

confidence: 96%

“…In effect, etoposide is one of the major nonalkylating agents in current use for high-dose chemotherapy (Jones et al 1995). Pharmacokinetics of etoposide have been reported to be dose-linear (Hande et al 1984;Newman et al 1988;Slevin 1991;Köhl et al 1992;Würthwein and Boos 2001). So far, the relationship between drug dose and pharmacokinetic parameters has been established by use of the data generated from different populations who were treated with varying doses, while an intraindividual comparison (which has the advantage of excluding the problem of between-patient variability as a confounding factor) has not yet been performed.…”

Section: Introductionmentioning

confidence: 97%

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Pharmacokinetics of intravenous etoposide in patients with breast cancer: influence of dose escalation and cyclophosphamide and doxorubicin coadministration

Busse

Würthwein

Hinske

et al. 2002

Naunyn-Schmiedeberg's Archives of Pharmacology

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This study investigates the impact of dose escalation and of doxorubicin and cyclophosphamide coadministration on the pharmacokinetics of etoposide (ETO). Pharmacokinetics of ETO were analyzed in seven patients with breast cancer receiving 3-4 cycles of conventional-dose (CD) and one final course of high-dose (HD) chemotherapy including ETO (450 mg/m(2) and 2100 mg/m(2), respectively, fractionated over 3 consecutive days). ETO was given as monoinfusion apart from day 1 of CD, where cyclophosphamide and doxorubicin were coadministered. Plasma samples obtained on day 1 and day 2 of CD- and HD-therapy, respectively, were analyzed for ETO by HPLC. Data from a total of 25 cycles of CD- and 7 cycles of HD-therapy are given as means +/- SD for CD-day 1, CD-day 2, HD-day 1 and HD-day 2, respectively. Following administration of 210+/-29, 278+/-41, 1143+/-79 and 1143+/-79 mg ETO, the AUC (0-24 h, normalized to 150 mg/m(2)) was 123+/-23, 113+/-22, 92+/-11 and 100+/-22 microgxh/ml. The AUC and CL of single-agent ETO were not significantly different between CD (day 2) and both days of HD ETO. However, we observed a modest but significant difference for AUC and CL between day 1 of CD (coadministration of doxorubicin and cyclophosphamide) and day 2 of CD (ETO monoinfusion), the AUC and CL being 9% higher (see above) and 10% lower (21.1 vs. 23.3 ml/minxm(2)) ( P<0.05), respectively, on day 1. The fraction of unbound ETO was similar on all occasions (range: 5.5%-6.6%). Interpatient variability for AUC and CL during CD-therapy was moderate with coefficients of variation (CV) of 17%-20%, while intraindividual variability was comparatively high and almost in the same range (CV of 13%-16%). Pharmacokinetics of etoposide were not significantly altered following fivefold dose escalation in the same patients. A 10% decrease in systemic clearance of etoposide was observed during doxorubicin and cyclophosphamide coadministration, which could result from drug interactions affecting renal and/or metabolic elimination of etoposide. The magnitude of the decrease, however, is unlikely to be of clinical significance.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 97%

Pharmacokinetics of intravenous etoposide in patients with breast cancer: influence of dose escalation and cyclophosphamide and doxorubicin coadministration

Busse

Würthwein

Hinske

et al. 2002

Naunyn-Schmiedeberg's Archives of Pharmacology

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“…We used etoposide phosphate, as it is widely used in oncology and hematology, often with dose intensification. Furthermore, etoposide, which is used over a wide range of dosages, has been shown to have a half-life independent of dosage and an area under the curve (AUC) proportional to the dose (8). The dosage in connection with stem cell transplantation is equivalent to 30-40 mg/kg but is given in combination with intensive doses of three other cytotoxic drugs.…”

Section: Discussionmentioning

confidence: 99%

Early Disturbance of Microvascular Function Precedes Chemotherapy-Induced Intestinal Injury

et al. 2005

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Intestinal injury 4-48 hr after cytotoxic therapy (etoposide phosphate, 100 mg/kg body weight [bw], intravenously [i.v.]) was studied in rats using ligated intestinal loops. Chromium-51 ethylenediaminetetraacetic acid ((51)Cr-EDTA) and rubidium-86 chloride ((86)RbCl) were deposited intraluminally to determine the extent of the increase in intestinal permeability and ion channel disruption. Evans Blue (EB) was used for detection of endothelial leakage. Intestinal morphology was documented. Endothelial dysfunction, as observed by an increased extravasation of EB, was evident already 4 hr after cytotoxic therapy. Intestinal epithelial injury, as observed by an increase in (51)Cr-EDTA permeation and a decrease in (86)Rb absorption, occurred after 48 hr. Finally, histology disclosed a reduced crypt cell proliferation, displayed as a decrease in Ki67-positive cells. The findings suggest that, in the development of intestinal injury after cytotoxic therapy, endothelial disruption is an early event, whereafter epithelial dysfunction and crypt stem cell arrest occur. This knowledge could be of importance in the design of future intervention trials.

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“…Etoposide is a semisynthetic derivative of podophyilotoxin and has proven activity in both myeloid and lymphoid malignancies including efficacy in standard doses in relapsed haematologic disease [22-241 and in high doses followed by marrow rescue [9,. It demonstrates linear pharmacokinetics [29] and penetrates the CSF after high-dose intravenous administration [30]. Phase 1 and 2 studies have shown dose-limiting toxicity at 50-70 mg/kg ideal body weight [31,32].…”

Section: Discussionmentioning

confidence: 99%

Intensive conditioning regimen for bone marrow transplantation in children with high‐risk haematological malignancies

Cole

Pritchard

Rogers

et al. 1994

Med. Pediatr. Oncol.

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Between September 1987 and May 1991, 21 children aged 10 months to 15 years (median 9 years) underwent bone marrow transplantation (BMT) for advanced haematological malignancies using a conditioning regimen consisting of total body irradiation (TBI), etoposide 1.8 g/m2 by continuous infusion, and cyclophosphamide 2 g/m2 on 3 consecutive days. The patients included 14 with acute lymphoblastic leukaemia (ALL), 1 with chronic myeloid leukaemia (CML), 1 with juvenile CML, 4 with non-Hodgkin's lymphoma and 1 with acute nonlymphocytic leukaemia. Eleven had an allogeneic BMT from an HLA-matched sibling, and 1 from an unrelated donor. Nine patients received 4-hydroperoxycyclophosphamide purged autologous marrow. Median time to myeloid engraftment (ANC> 500/microliters) was 19 days in allogeneic BMT patients and 28 days in autologous BMT patients (P < .01). Mucositis was the major regimen-related toxicity (RRT). GI toxicity in the form of diarrhoea affected ten patients and five had veno-occlusive disease of the liver. Two patients had mild bladder toxicity and one died of renal toxicity. There was no CNS or cardiac toxicity. There was no significant difference in the incidence of toxicity according to the type of BMT (autologous or allogeneic), total dose, or sequence of TBI. With a median follow-up of 44 months, ten patients are alive (6/12 allogeneic BMT patients and 4/9 autologous BMT patients). Of the 11 deaths, four were related to toxicity (2 aspergillus, 1 haemorrhage following liver biopsy, and 1 from haemolytic-uraemic syndrome), and 4/12 allogeneic and 4/9 autologous BMT patients died from relapsed disease. This conditioning regimen is well tolerated in children, demonstrating mild and reversible RRT.

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Pharmacokinetics of high-dose etoposide

Cited by 26 publications

References 1 publication

Pharmacokinetics of intravenous etoposide in patients with breast cancer: influence of dose escalation and cyclophosphamide and doxorubicin coadministration

Pharmacokinetics of intravenous etoposide in patients with breast cancer: influence of dose escalation and cyclophosphamide and doxorubicin coadministration

Early Disturbance of Microvascular Function Precedes Chemotherapy-Induced Intestinal Injury

Intensive conditioning regimen for bone marrow transplantation in children with high‐risk haematological malignancies

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