Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 6/2004

01-12-2004 | Original Article

Pharmacokinetic studies of 9-nitrocamptothecin on intermittent and continuous schedules of administration in patients with solid tumors

Authors: Laura L. Jung, Ramesh K. Ramanathan, Merrill J. Egorin, Ruzhi Jin, Chandra P. Belani, Douglas M. Potter, Sandra Strychor, Donald L. Trump, Christine Walko, Marwan Fakih, William C. Zamboni

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2004

Login to get access

Abstract

Purpose

Oral administration of 9-nitrocamptothecin (9NC), and the formation of its metabolite 9-aminocamptothecin (9AC), may be associated with high interpatient and intrapatient variability. Therefore, we evaluated the plasma pharmacokinetics and urine recovery of 9NC administered on three different schedules as part of phase I and phase II studies.

Experimental design

In phase I schedule A, 9NC was administered orally daily for 5 days per week for 2 weeks repeated every 4 weeks. On phase I schedule B, 9NC was administered daily for 14 days repeated every 4 weeks. In Phase II, 9NC was administered daily for 5 days during 8 weeks (one cycle). Serial blood samples were obtained on day 1 and day 10 or 11 for phase I studies, and day 1 and day 50 for the phase II study. Recovery of 9NC and 9AC in urine was evaluated on day 1 and day 10 or 11 in the phase I study. Area under the 9NC and 9AC plasma concentration vs time curves from 0 to 24 h (AUC0–24 h) were calculated using compartmental analysis.

Results

The mean±SD 9NC lactone AUC0–24 h values on day 1 at the maximum tolerated dose of schedules A and B (2.43 and 1.70 mg/m2, respectively) and the phase II dose (1.5 mg/m2) were 78.9±54.4, 155.7±112.8, and 48.3±17.5 ng/ml·h, respectively. The mean±SD 9AC lactone AUC0–24 h values at these same doses of 9NC were 17.3±17.9, 41.3±16.6, and 31.3±12.8 ng/ml h, respectively. The ratios of 9NC lactone AUC0–24 h on day 10 or 11 to day 1 on phase I A and B were 1.27±0.68 and 1.73±1.56, respectively, and the ratios 9AC lactone AUC0–24 h on day 10 or 11 to day 1 on phase I A and B were 2.23±1.02 and 1.65±0.97, respectively. The recovery of 9NC and 9AC in the urine was <15%.

Conclusions

There was significant interpatient and intrapatient variability in the disposition of 9NC and 9AC. 9NC and 9AC undergo primarily nonrenal elimination.
Literature
1.
Hsiang YH, Hertzberg R, Hecht S, Liu LF (1985) Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 260:14873
2.
Covey JM, Jaxel C, Kohn KW, Pommier Y (1989) Protein-linked DNA strand breaks induced in mammalian cells by camptothecin, an inhibitor of topoisomerase I. Cancer Res 49:5016PubMed
3.
Jaxel C, Kohn KW, Wani MC, Wall ME, Pommier Y (1989) Structure-activity study of the actions of camptothecin derivatives on mammalian topoisomerase I: evidence for a specific receptor site and a relation to antitumor activity. Cancer Res 49:1465PubMed
4.
Kirstein MN, Houghton PJ, Cheshire PJ, Richmond LB, Smith AK, Hanna SK, Stewart CF (2001) Relation between 9-aminocamptothecin systemic exposure and tumor response in human solid tumor xenografts. Clin Cancer Res 7:358PubMed
5.
Pazdur R, Diaz-Canton E, Ballard WP, Bradof JE, Graham S, Arbuck SG, Abbruzzese JL, Winn R (1997) Phase II trial of 9-aminocamptothecin administered as a 72-hour continuous infusion in metastatic colorectal carcinoma. J Clin Oncol 15:2905PubMed
6.
Takimoto CH, Thomas R (2000) The clinical development of 9-aminocamptothecin. Ann N Y Acad Sci 922:224PubMed
7.
Furman WL, Stewart CF, Poquette CA, Pratt CB, Santana VM, Zamboni WC, Bowman LC, Ma MK, Hoffer FA, Meyer WH, Pappo AS, Walter AW, Houghton PJ (1999) Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children. J Clin Oncol 17:1815
8.
Thompson J, Zamboni WC, Cheshire PJ, Lutz L, Luo X, Li Y, Houghton JA, Stewart CF, Houghton PJ (1997) Efficacy of systemic administration of irinotecan against neuroblastoma xenografts. Clin Cancer Res 3:423PubMed
9.
Hsiang YH, Lihou MG, Liu LF (1989) Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res 49:5077PubMed
10.
Del Bino G, Darzynkiewicz Z (1991) Camptothecin, teniposide, or 4′-(9-acridinylamino)-3-methanesulfon-m-anisidide, but not mitoxantrone or doxorubicin, induces degradation of nuclear DNA in the S phase of HL-60 cells. Cancer Res 51:1165PubMed
11.
Houghton PJ, Cheshire PJ, Hallman JD, Lutz L, Friedman HS, Danks MK, Houghton JA (1995) Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol 36:393CrossRefPubMed
12.
Zamboni WC, Bowman LC, Tan M, Santana VM, Houghton PJ, Meyer WH, Pratt CB, Heideman RL, Gajjar AJ, Pappo AS, Stewart CF (1999) Interpatient variability in bioavailability of the intravenous formulation of topotecan given orally to children with recurrent solid tumors. Cancer Chemother Pharmacol 43:454CrossRefPubMed
13.
Gupta E, Luo F, Lallo A, Ramanathan S, Vyas V, Rubin E, Sinko P (2000) The intestinal absorption of camptothecin, a highly lipophilic drug, across Caco-2 cells is mediated by active transporter(s). Anticancer Res 20:1013PubMed
14.
Drengler RL, Kuhn JG, Schaaf LJ, Rodriguez GI, Villalona-Calero MA, Hammond LA, Stephenson JA Jr, Hodges S, Kraynak MA, Staton BA, Elfring GL, Locker PK, Miller LL, Von Hoff DD, Rothenberg ML (1999) Phase I and pharmacokinetic trial of oral irinotecan administered daily for 5 days every 3 weeks in patients with solid tumors. J Clin Oncol 17:685
15.
Loos WJ, Gelderblom H, Sparreboom A, Verweij J, de Jonge MJ (2000) Inter- and intrapatient variability in oral topotecan pharmacokinetics: implications for body-surface area dosage regimens. Clin Cancer Res 6:2685PubMed
16.
Kruijtzer CM, Beijnen JH, Rosing H, Bokkel Huinink WW, Schot M, Jewell RC, Paul EM, Schellens JH (2002) Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. J Clin Oncol 20:2943CrossRefPubMed
17.
Akhtar S, Beckman RA, Mould DR, Doyle E, Fields SZ, Wright J (2000) Pretreatment with ranitidine does not reduce the bioavailability of orally administered topotecan. Cancer Chemother Pharmacol 46:204CrossRefPubMed
18.
Mi Z, Burke TG (1994) Differential interactions of camptothecin lactone and carboxylate forms with human blood components. Biochemistry 33:10325
19.
Mi Z, Burke TG (1994) Marked interspecies variations concerning the interactions of camptothecin with serum albumins: a frequency-domain fluorescence spectroscopic study. Biochemistry 33:12540
20.
Schrijvers D, Highley M, De Bruyn E, Van Oosterom AT, Vermorken JB (1999) Role of red blood cells in pharmacokinetics of chemotherapeutic agents. Anticancer Drugs 10:147PubMed
21.
Schoemaker NE, Mathot RAA, Schoffski P, Rosing H, Schellens JHM, Beijnen JH (2002) Development of an optimal pharmacokinetic sampling schedule for rubitecan administered orally in a daily times five schedule. Cancer Chemother Pharmacol 50:514–517CrossRefPubMed
22.
Raymond D, Campone M, Stupp R, Menten J, Chollet P, Lesimple T, Fety-Deporte R, Lacombe D, Paoletti X, Fumoleau P (2002) Multicentre phase II and pharmacokinetic study of RFS2000 (9-nitrocamptothecin) administered orally 5 days a week in patients with glioblastoma multiforme. Eur J Cancer 38:1348–1350CrossRefPubMed
23.
Schoffski P, Herr A, Vermorken JB, Van den BJ, Beijnen JH, Rosing H, Volk J, Ganser A, Adank S, Botma HJ, Wanders J (2002) Clinical phase II study and pharmacological evaluation of rubitecan in non-pretreated patients with metastatic colorectal cancer—significant effect of food intake on the bioavailability of the oral camptothecin analogue. Eur J Cancer 38:807CrossRefPubMed
24.
Natelson EA, Giovanella BC, Verschraegen CF, Fehir KM, De Ipolyi PD, Harris N, Stehlin JS (1996) Phase I clinical and pharmacological studies of 20-(S)-camptothecin and 20-(S)-9-nitrocamptothecin as anticancer agents. Ann N Y Acad Sci 803:224PubMed
25.
Zamboni WC, Jung LL, Egorin MJ, Potter DM, Friedland DM, Belani CP, Agarwala SS, Wong MM, Fakih M, Trump DL, Jin R, Strychor S, Vozniak M, Troetschel M, Ramanathan RK (2004) Phase I and pharmacologic study of intermittently administered 9-nitrocamptothecin in patients with advanced solid tumors. Clin Cancer Res 10:5058PubMed
26.
Potter DM (2002) Adaptive dose finding for phase I clinical trials of drugs used for chemotherapy of cancer. Stat Med 21:1805CrossRefPubMed
27.
O’Quigley J, Pepe M, Fisher L (1990) Continual reassessment method: a practical design for phase 1 clinical trials in cancer. Biometrics 46:33PubMed
28.
Supko JG, Malspeis L (1992) Liquid chromatographic analysis of 9-aminocamptothecin in plasma monitored by fluorescence induced upon post-column acidification. J Liquid Chromatogr 15:3261
29.
D’Argenio DZ, Schmuitzky A (1997) ADAPT II user’s guide. Biomedical Simulation Resource, University of Southern California, Los Angeles
30.
Rowland M, Tozer T (eds) (1999) Clinical pharmacokinetics: concepts and applications. Lea and Febiger, Philadelphia
31.
Verschraegen CF, Gilbert BE, Huaringa AJ, Newman R, Harris N, Leyva FJ, Keus L, Campbell K, Nelson-Taylor T, Knight V (2000) Feasibility, phase I, and pharmacological study of aerosolized liposomal 9-nitro-20(S)-camptothecin in patients with advanced malignancies in the lungs. Ann N Y Acad Sci 922:352PubMed
32.
Gilbert BE, Newman R, Zamboni WC, Knight V, Verschraegen CF (2001) Pharmacokinetics of multiple 9-nitro-camptothecin (9NC) liposome aerosols during a Phase I study: levels of total and lactone forms, and its conversion to 9-amino-camptothecin (9AC). Proc Am Soc Clin Onc 20:90b
33.
Gounder M, Saleem A, Roychowdhury M (2002) Metabolism of 9-nitrocamptothecin (RFS2000/9NC) to 9-aminocamptothecin (9AC) in patients and in vitro. Proc Am Assoc Cancer Res 42
34.
Pantazis P, Harris N, Mendoza J, Giovanella B (1995) The role of pH and serum albumin in the metabolic conversion of 9-nitrocamptothecin to 9-aminocamptothecin by human hematopoietic and other cells. Eur J Haematol 55:211PubMed
35.
Hinz HR, Harris NJ, Natelson EA, Giovanella BC (1994) Pharmacokinetics of the in vivo and in vitro conversion of 9-nitro-20(S)-camptothecin to 9-amino-20(S)-camptothecin in humans, dogs, and mice. Cancer Res 54:3096PubMed
Metadata
Title
Pharmacokinetic studies of 9-nitrocamptothecin on intermittent and continuous schedules of administration in patients with solid tumors
Authors
Laura L. Jung
Ramesh K. Ramanathan
Merrill J. Egorin
Ruzhi Jin
Chandra P. Belani
Douglas M. Potter
Sandra Strychor
Donald L. Trump
Christine Walko
Marwan Fakih
William C. Zamboni
Publication date
01-12-2004
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 6/2004
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-004-0835-9

Other articles of this Issue 6/2004

Cancer Chemotherapy and Pharmacology 6/2004 Go to the issue

Original Article

A phase I trial of gemcitabine plus cladribine in patients with advanced hematologic malignant diseases

Original Article

Phase II study of irinotecan combined with carboplatin in previously untreated non-small-cell lung cancer

Original Article

Pharmacokinetics of liposomal doxorubicin (TLC-D99; Myocet) in patients with solid tumors: an open-label, single-dose study

Original Article

Synergistic killing of human leukemia cells by antioxidants and trichostatin A

Original Article

A 150-kDa glycoprotein isolated from Solanum nigrum L. has cytotoxic and apoptotic effects by inhibiting the effects of protein kinase C alpha, nuclear factor-kappa B and inducible nitric oxide in HCT-116 cells

Original Article

Evaluation of the cassette dosing approach for assessing the pharmacokinetics of geldanamycin analogues in mice
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits