Clinical and pharmacokinetic study of oral NK611, a new podophyllotoxin derivative

O. Pagani, M. Zucchetti, C. Sessa, J. De Jong, M. D'Incalci, M. De Fusco, A. Kaeser-Fröhlich, A. Hanauske, F. Cavalli

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

NK611 is a novel water-soluble podophyllotoxin derivative that has comparable antitumour activity but higher potency and better bioavailability in animals as compared with etoposide. The primary objectives of this study were to determine, after both oral and intravenous administration in the same patient, the bioavailability and the pharmacokinetic profile of NK611. Secondary objectives involved evaluation of the toxicity and the antitumor activity. Patients were randomly assigned to receive oral or intravenous (30-min infusion) doses of 5, 10, and 20 mg/m2 on day 1, when pharmacokinetic studies were performed. A daily oral dose of 20 mg/m2 was then given from day 4 through day 7 for respective total doses of 85, 90, and 100 mg/m2. NK611 and its metabolites were determined in plasma and urine by two different high-performance liquid chromatography (HPLC) methods with UV detection. A total of 21 adult patients entered the study and received the complete first cycle and at least the 1st day of cycle 2; 17 of them received at least 2 complete cycles of treatment. After intravenous administration, the plasma decay curve of NK611 followed a two-exponential model, and after oral administration it declined monoexponentially in most cases. At all dose levels, bioavailability values were around 100%. At concentrations between 10 and 20 mg/m2 after both routes of administration, the pharmacokinetics were nonlinear; the terminal half-life, plasma clearance, and volume of distribution were significantly different; and the area under the plasma concentration-time curve was not correlated to the dose. The urinary excretion of NK611 corresponded to 10-15% of the dose after administration by both routes, whereas that of N-demethyl NK611 and its picroform was highly variable. The features of neutropenia were comparable with those noted for etoposide involving a high degree of interpatient variability and recovery within 1 month after treatment. A daily dose of 20 mg/m2 for 5 consecutive days every 4 weeks is the recommended regimen for phase II studies in patients who have never been treated or have undergone previous chemotherapy only once.

Original languageEnglish
Pages (from-to)541-547
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume38
Issue number6
DOIs
Publication statusPublished - 1996

Fingerprint

Podophyllotoxin
Pharmacokinetics
Derivatives
Biological Availability
Plasmas
Etoposide
Intravenous Administration
Oral Administration
Chemotherapy
Plasma Volume
High performance liquid chromatography
Metabolites
Neutropenia
Half-Life
Toxicity
NK 611
Clinical Studies
Animals
High Pressure Liquid Chromatography
Urine

Keywords

  • Bioavailability
  • Pharmacokinetics
  • Podophyllotoxin derivative

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology

Cite this

Clinical and pharmacokinetic study of oral NK611, a new podophyllotoxin derivative. / Pagani, O.; Zucchetti, M.; Sessa, C.; De Jong, J.; D'Incalci, M.; De Fusco, M.; Kaeser-Fröhlich, A.; Hanauske, A.; Cavalli, F.

In: Cancer Chemotherapy and Pharmacology, Vol. 38, No. 6, 1996, p. 541-547.

Research output: Contribution to journalArticle

Pagani, O, Zucchetti, M, Sessa, C, De Jong, J, D'Incalci, M, De Fusco, M, Kaeser-Fröhlich, A, Hanauske, A & Cavalli, F 1996, 'Clinical and pharmacokinetic study of oral NK611, a new podophyllotoxin derivative', Cancer Chemotherapy and Pharmacology, vol. 38, no. 6, pp. 541-547. https://doi.org/10.1007/s002800050524
Pagani, O. ; Zucchetti, M. ; Sessa, C. ; De Jong, J. ; D'Incalci, M. ; De Fusco, M. ; Kaeser-Fröhlich, A. ; Hanauske, A. ; Cavalli, F. / Clinical and pharmacokinetic study of oral NK611, a new podophyllotoxin derivative. In: Cancer Chemotherapy and Pharmacology. 1996 ; Vol. 38, No. 6. pp. 541-547.
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AU - Sessa, C.

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AU - D'Incalci, M.

AU - De Fusco, M.

AU - Kaeser-Fröhlich, A.

AU - Hanauske, A.

AU - Cavalli, F.

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