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  • 1
    Electronic Resource
    Electronic Resource
    Interpatient variability in bioavailability of the intravenous formulation of topotecan given orally to children with recurrent solid tumors (1999)
    Springer
    Cancer chemotherapy and pharmacology 43 (1999), S. 454-460 
    Details
    ISSN: 1432-0843
    Keywords: Key words Topotecan ; Oral bioavailability ; Pediatric solid tumors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: Evaluation of inter- and intrapatient variability of topotecan oral bioavailability and disposition was performed in children with malignant solid tumors. Patients and methods: Topotecan i.v. formulation was given orally on schedules of daily for 21 consecutive days (d × 21) or daily for 5 days per week for 3 weeks [(d × 5)3], in both cases repeated every 28 days. Topotecan doses of 0.8 and 1.1 mg/m2 per day were evaluated on both schedules. Serial plasma samples were obtained after oral and i.v. administration of topotecan at the beginning and end of the first course of therapy. Topotecan lactone and total concentrations were measured by a high-performance liquid chromatography (HPLC) assay, and a one-or two-compartment model was fit to the plasma concentration-time data after oral or i.v. administration, respectively. Topotecan oral bioavailability (F) was calculated as the ratio of the AUC determined after oral treatment (AUCpo) divided by the AUC calculated after i.v. administration. Results: Pharmacokinetics studies were performed on 15 and 11 patients receiving 0.8 and 1.1 mg/m2 per day, respectively. After oral administration the topotecan lactone AUCpo and F determined for 0.8 and 1.1 mg/m2 per day were 13.6 ± 5.8 and 25.1 ± 12.9 ng ml−1 h and 0.34 ± 0.14 and 0.34 ± 0.16, respectively. The within-patient variance for AUCpo and F was much smaller than the between-patient variance. The ratio of topotecan lactone to total concentration was consistently higher after oral as compared with i.v. administration. Conclusions: Large interpatient variability was noted in topotecan pharmacokinetics, whereas intrapatient variability was relatively small. Further studies of oral topotecan are warranted to evaluate the tolerance of shorter courses and to define further the interpatient variability.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050923
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  • 2
    Electronic Resource
    Electronic Resource
    Clinical effects and pharmacokinetics of the fusion protein PIXY321 in children receiving myelosuppressive chemotherapy (1997)
    Springer
    Cancer chemotherapy and pharmacology 41 (1997), S. 229-236 
    Details
    ISSN: 1432-0843
    Keywords: Key words Pharmacokinetics ; Children ; Solid tumors ; PIXY321
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A hemopoietin with the ability to accelerate both platelet and granulocyte recovery after intensive chemotherapy would have great clinical utility. The recombinant fusion protein composed of human granulocyte-macrophage colony-stimulating factor and interleukin-3 (PIXY321), showed some promise in early adult trials. However, studies for pediatric patients are limited, and there are no systematic data on the pharmacokinetics of PIXY321 given over prolonged periods at current dosage levels. Purpose: To determine the safety, clinical effects and plasma concentrations of increasing doses of PIXY321 in children treated with myelosuppressive chemotherapy. Methods: A total of 39 children with relapsed or high-risk solid tumors were enrolled in this phase I/II study. PIXY321 was administered once or twice daily by subcutaneous injection in total doses of 500 to 1000 μg/m2 per day for 14 days after each course of chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). Pharmacokinetic studies were performed on day 1 of the first course in 33 patients and repeated on day 14 in 13 patients (once-daily schedule only). Results: Although mild local skin reactions and fever were frequent, no dose-limiting toxicity was identified at the maximum dose studied (1000 μg/m2 per day). There were no statistically significant differences in chemotherapy-induced hematologic toxicity with increasing doses of PIXY321 or with twice-daily vs once-daily dosing. On day 1, the median PIXY321 clearance was 657 ml/min per m2 (range 77–1804 ml/min per m2) and the median half-life was 3.7 h (range 2.1–20.8 h). On day 14, clearance increased in all patients studied (median increase 63%), with a corresponding decrease in the median 12-h concentration (from 1.2 to 0.25 ng/ml). Maximum concentrations were 〈1 ng/ml in 81% of patients, and only two patients had maximum plasma concentrations equivalent to those required for consistent activity in vitro. Conclusions: The recombinant fusion protein PIXY321 proved safe in children treated with myelosuppressive ICE chemotherapy but had no demonstrable clinical benefits. The pharmacokinetic studies suggest that the observed lack of hematologic benefit may be explained by low plasma concentrations resulting from increased clearance with prolonged administration. Moreover, the significant increase in PIXY321 systemic clearance in the absence of increased circulating myeloid cells suggests that the upregulation of either extravascular compartment hematopoietic progenitor cells or nonhematopoietic cells may play an important role in controlling circulating concentrations of this unique cytokine. These findings highlight the importance of a thorough assessment of the systemic disposition of cytokines when determining the dose and schedule necessary to achieve clinical activity in patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050733
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  • 3
    Electronic Resource
    Electronic Resource
    Malignant melanoma in children: imaging spectrum (1996)
    Springer
    Pediatric radiology 26 (1996), S. 800-805 
    Details
    ISSN: 1432-1998
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objective. The objective of this study was to investigate the role of diagnostic imaging in detecting unsuspected metastatic disease in children with malignant melanoma. This has not been well studied previously. Materials and methods. We correlated imaging findings of 33 children diagnosed with melanoma with the level of invasion and clinical stage of disease. Results. Clinically undetectable metastases were identified in eight patients (25 %), four of whom had multiple metastases. All eight patients had deep lesions (Clark's level IV or V) or unknown primary sites of disease. Conclusion. Children with thick melanomas and those with unknown site of primary tumors are at increased risk of having clinically unsuspected metastases and should undergo CT of the chest, abdomen, and local-regional nodal basins at diagnosis to determine disease extent.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01396205
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  • 4
    Electronic Resource
    Electronic Resource
    New drug development for pediatric oncology (1996)
    Springer
    Investigational new drugs 14 (1996), S. 1-10 
    Details
    ISSN: 1573-0646
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00173677
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  • 5
    Electronic Resource
    Electronic Resource
    Topoisomerase I interactive drugs in children with cancer (1996)
    Springer
    Investigational new drugs 14 (1996), S. 37-47 
    Details
    ISSN: 1573-0646
    Keywords: camptothecin ; topotecan ; irinotecan ; pediatric oncology ; DNA topoisomerase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Topotecan, irinotecan, and 9-aminocamptothecin (9-AC) are analogs of the plant alkaloid 20(S)-camptothecin (CMT), the prototypical DNA topoisomerase I interactive agent. These agents interact with the topoisomerase I-DNA complex and prevent resealing topoisomerase I-mediated DNA single-strand breaks. This eventual leads to double-strand DNA breaks and apoptosis or cell death. Topotecan, irinotecan, and 9-AC have shown significant activity in mice bearing pediatric solid tumor xenografts; the greatest antitumor responses were found with protracted continuous schedules. Preclinical data also suggest that maintenance of an exposure-duration threshold (EDT) may be required to achieve optimal cytotoxicity. Pediatric Phase I trials have evaluated the toxicity and safety of camptothecin analogs in children with relapsed solid tumors and relapsed acute leukemia. The primary dose-limiting toxicity (DLT) for the CMT analogs in children has been myelosuppression, except for mucositis observed with the 120-hr continuous topotecan infusion schedule. Pharmacodynamic relationships with these analogs have been reported between systemic exposure, and myelosuppression and mucositis. Although not a primary objective of the early Phase I studies, antitumor responses have been reported. In this review, the pharmacokinetics and pharmacodynamics of the CMT analogs studied in children are summarized, and future studies of these agents are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00173681
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  • 6
    Electronic Resource
    Electronic Resource
    Phase I study of DMP 840 in pediatric patients with refractory solid tumors (1998)
    Springer
    Investigational new drugs 16 (1998), S. 45-49 
    Details
    ISSN: 1573-0646
    Keywords: DMP 840 ; pediatric tumors ; phase I study
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The bis-naphthalimide DMP 840 has demonstrated high level antitumor activity in a number of preclinical models and has been evaluated in several Phase I studies in adults. We enrolled 10 patients with refractory pediatric solid tumors to this Phase I study of DMP 840 given intravenously by short infusion daily for 5 days. The most frequent and dose-limiting toxicity was myelosuppression. The maximum tolerated dose on this schedule was 8.6 mg/m2 daily for 5 days. One patient had a complete response; there were no measurable tumor responses among the remaining 9 patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006014510078
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