Steady-state levels and bone marrow toxicity of etoposide in children and infants: does etoposide require age-dependent dose calculation?

PURPOSE: Most pediatric treatment protocols specify dose calculations for cytostatic drugs based on body-surface area (BSA). However, for children less than 1 year of age, calculation guidelines vary. Normally, reduced dosages are recommended with calculations based on body weight (BW). However, the optimal dose for infants should take age-dependent and drug-specific pharmacokinetic parameters into account. PATIENTS AND METHODS: The current investigation focused on the effects of different dose-reduction rules on the steady-state levels (Css) of etoposide and related bone marrow toxicity. One hundred seventy three treatment courses in 78 children on a 96-hour continuous infusion schedule were monitored for Css (determined by high-performance liquid chromatography [HPLC]), and 100 courses were documented in detail with regard to dose calculation (125 mg/m2, 4.17/kg, or 2/3 x 4.17/kg) and toxicity. RESULTS: Dose calculation on the basis of BSA led to Css of 4.9 +/- 1.2 micrograms/mL, which on the basis of BW was 3.5 +/- 1.1 micrograms/mL and 1.95 +/- 0.6 micrograms/mL (2/3.kg-dose), respectively. However, conversion of the latter levels to those expected with the regular square-meter-dose, resulted in values of 4.7 +/- 1.4 micrograms/mL and 4.2 +/- 1.2 micrograms/mL (/125 mg/m2). Lower etoposide Css levels resulted in less pronounced thrombocyte and WBC nadirs in the respective groups. The dose-calculation rules for infants, therefore, decreased both dose-intensity and related toxicity. Etoposide clearance rates related to BW (0.8 +/- 0.3 mL/min/kg) or BW (19 +/- 6 mL/min/m2) did not show any differences between children and infants, even in the age range of 3 to 12 months. CONCLUSION: In the case of etoposide, special dose-calculation guidelines for infants are not substantiated by age-dependent pharmacokinetics or tolerance.

Blood flow and steady state temperatures in deep-seated tumors and normal tissues.

Blood flow related data obtained in different deep-seated tumors and adjacent normal tissues were analyzed in 28 patients who were treated with combined regional hyperthermia and radiation for recurrent or metastatic tumors. The evaluation of blood flow related data has been made using the thermal clearance/thermal cooling coefficient technique and dynamic computed tomography. With both methods significant differences in global perfusion have been observed between tumor center and tumor periphery, between tumor and normal tissue (deep muscle and fat tissue), and between tumor entities. Washout rates or thermal cooling coefficient values, as well as the enhancement of contrast material over baseline (expressed in delta Hounsfield Units), correlated significantly with the achieved steady state temperatures for different tissue categories (i.e., tumor center, tumor periphery, different tumor entities, normal tissue). Thermal cooling coefficient values higher than 63000-83000 W/m3-K (washout rates higher than 15-20 ml/100 g-min) or values of enhancement of contrast material higher than delta 20-25 HU coincide with a limitation in achieving therapeutic temperatures higher than 40 degrees C.

Pharmacokinetics of trofosfamide and its dechloroethylated metabolites.

To contribute to effective and safe outpatient treatment, we investigated the metabolism of trofosfamide (Trofo) after oral administration. We analyzed Trofo metabolism in 15 patients aged from 3 to 73 years who were treated with 150 or 250 mg/m2 Trofo in combination with etoposide. Serum samples were collected with 13 patients after oral administration, and Trofo and its dechloroethylated metabolites were quantified by gas chromatography. Urine samples were collected from five patients and analyzed by same method. Ifosfamide (Ifo) was the main metabolite in serum and urine (AUCTrofo:AUCIfo 1:13), whereas cyclophosphamide (Cyclo) was formed in smaller amounts (AUC(Ifo):AUC(Cyclo) 18:1). Ifo and Cyclo were further oxidized in the chloroethyl side chains to form 2- and 3-dechlorethylifosfamide in varying quantities. The urinary excretion of Trofo and its dechloroethylated metabolites amounted to about 10% of the total dose. Our results confirm former in vitro observations about the metabolism of Trofo. The main side-chain metabolites Ifo and Cyclo can be further activated by oxidation and formation of their respective phosphoramide mustards. Hence, Trofo is an interesting agent for oral chemotherapy.

Determination of paclitaxel in biological fluids by micellar electrokinetic chromatography.

A method has been developed for the determination of paclitaxel (Taxol) in plasma and urine using capillary electrophoresis with sodium dodecyl sulfate as additive in the run buffer. The samples are extracted and preconcentrated with tert.-butyl methyl ether. Taxotere has been used as the internal standard. The limit of detection of paclitaxel is 20 ng/ml. In comparison to high-performance liquid chromatography, the capillary electrophoresis method is simple and needs less organic solvents.

Effect of amifostine on neuroblastoma during high dose chemotherapy: in vivo and in vitro investigations.

Amifostine (Ethyol, WR-2721) has been clinically used in combination with high dose therapy of neuroblastoma stage 4 with melphalan, carboplatin and VP-16 in 14 patients. The amifostine group was compared to a historical control group of 24 comparably-treated patients. There were no significant differences regarding the time of hematological recovery, the duration of hospitalization, the duration of antibiotic treatment and the extent of renal toxicity. However, in contrast to four patients of the control group, no patient in the amifostine group developed such severe mucositis that artificial ventilation became necessary. Pretreatment of neuroblastoma cell lines for 30 minutes with amifostine and the free thiol(WR-1065) did not reduce the cytotoxic effects of melphalan, carboplatin and VP-16. Evidence was obtained that the uptake of the activated thiol could be achieved by a polyamine transporter. Taken together, the data do not support the use of amifostine in high dose chemotherapy of neuroblastoma prior to autologous stem cell transplantation. However, amifostine may be more effective in conventional neuroblastoma therapy where protection of bone marrow stem cells is necessary.

[Pharmacokinetic aspects of oral administration of etoposide]. / Pharmakokinetische Aspekte der oralen Applikation von Etoposid.

BACKGROUND: Etoposide is a cytotoxic agent which is frequently employed in paediatric oncology and which is available for intravenous as well as oral application. Many advantages of the formulation for oral use have been opposed by concerns about its interindividually varying bioavailability. The influence of the dosage of etoposide on its activity and toxicity ("schedule dependency") has also been discussed. The present paper deals with the pharmacokinetics of oral etoposide focusing on the interindividual variability. PATIENTS: Sixteen patients aged between 3 and 73 years received oral etoposide at a dosage of 28 mg/m2 to 149 mg/m2 in combination with oral trofosfamide for palliation. METHOD: HPLC was used to measure total and free serum etoposide in 16 patients, and the etoposide concentration in several urine samples from 8 patients. Pharmacokinetic parameters were normalized to a dosage of 100 mg/m2. RESULTS: The peak serum concentration, the time to peak concentration, the area under the concentration-time curve, the terminal half-life and the apparent clearance after oral application were calculated to be 6.7 micrograms/ml, 2.1 h, 51.8 (microgram.h/ml)/(100 mg/m2), 5.6 h, and 40.3 ml/min for total etoposide, and 0.23 microgram/ml, 1.9 h, 1.76 (microgram.h/ml)/ (100 mg/m2), 5.9 h, and 1172 ml/min for free serum etoposide, respectively. On an average, urinary recovery of etoposide was 21% of the oral dose. The fraction of free etoposide was calculated to be close to 4%. Regarding the systemic exposure to etoposide, a variation coefficient of 40% was determined. Additional studies showed that the interindividual variability mainly concerned the peak levels, while the duration for which intermediate etoposide levels were maintained varied less between individuals. On simulating different dosage schedules, it was seen that the duration of intermediate concentrations (0.5-2 micrograms/ml) may be extended significantly by dividing the daily dose of etoposide into two oral applications. CONCLUSION: The total systemic exposure under oral etoposide treatment varies considerably between individuals. Extended intervals of intermediate etoposide concentration and less variation are, however, possible with oral therapy. Dividing the daily dose into two applications seems advisable. Future studies are warranted to test hypotheses on pharmacokinetic-pharmacodynamic aspects by pharmacological drug monitoring.

Population pharmacokinetic approach to compare oral and i.v. administration of etoposide.

The antitumor effect of etoposide (ETO) may be related to duration of exposure to a relatively low serum level while myelosuppression may be dependent on peak ETO serum levels. With regard to such therapeutic ranges, duration of exposure to predefined plasma ETO concentration ranges and the related AUC (expressed as percent of total AUC, pAUC) were used to compare pharmacokinetic profiles after oral and short time i.v. (1 h infusion) administration of identical ETO doses (100 mg/m2). Patients included in this study received i.v. (18 patients, short-term infusions) or oral (16 patients) ETO on different treatment schedules. Plasma ETO concentrations were determined by HPLC and population pharmacokinetic parameters were calculated (P-Pharm 1.4). Despite an 'apparent bioavailability' of 59%, oral administration of ETO was associated with the same time of exposure to a predefined 'therapeutic range' of 0.5-3 mg/l and a significantly higher pAUC compared to i.v. administration. By contrast, time of exposure to the probably more myelotoxic concentration range above 3 mg/l was significantly shorter and the related pAUC was highly significantly lower after oral than after i.v. administration. These findings demonstrate that oral ETO therapy is at least equivalent to short time i.v. therapy in terms of achieving specific target concentration ranges and avoiding peak concentrations.

Hepatic veno-occlusive disease in pediatric stem cell recipients: successful treatment with continuous infusion of prostaglandin E1 and low-dose heparin.

Limited data exist on therapeutic options for established hepatic veno-occlusive disease (VOD) in pediatric patients after stem cell transplantation (SCT). In this report, we present data on the successful treatment of VOD in three children following allogeneic SCT and report the duplex ultrasound criteria for the confirmation of the diagnosis and for the evaluation of the treatment progress. All patients were <2 years at the time of transplantation and had received preparative regimens containing busulfan and cyclophosphamide. There were no known pretransplant risk factors for VOD. Allogeneic stem cell transplantation was performed from a sibling donor for CMML and from unrelated donors for Wiskott-Aldrich syndrome and familial hemophagocytic lymphohistiocytosis (FHL). The onset of first clinical symptoms of VOD (as defined by the Seattle and Baltimore criteria) was relatively late in all three patients (days +19, +20, and +25, respectively). Time from onset of first symptoms until confirmation of diagnosis by serial duplex ultrasound examination was 4-11 days. Duplex ultrasound criteria are as follows: complete change of direction of blood flow in the portal vein, decrease of flow in the hepatic veins, and development of collateral circulation. Treatment was initiated upon confirmation of VOD by continuous infusion of prostaglandin E1 (initial dose 0.075 microg/kg/h) in addition to low-dose heparin (100 units/kg/d). Treatment was continued at the maximum tolerated dose of 0.3-0.5 microg/kg/h of PGE1. After 9, 14, and 25 days of treatment respectively, normal portal vein flow was restored and treatment could be discontinued. All three patients are alive and well without apparent sequelae.