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 4/2012

01-04-2012 | Original Article

Pharmacokinetic and pharmacodynamic study on amrubicin and amrubicinol in Japanese patients with lung cancer

Authors: Yoshinori Makino, Noboru Yamamoto, Hitoshi Sato, Reiko Ando, Yasushi Goto, Chiharu Tanai, Hajime Asahina, Hiroshi Nokihara, Ikuo Sekine, Hideo Kunitoh, Yuichiro Ohe, Erika Sugiyama, Nobuaki Yokote, Tomohide Tamura, Hiroshi Yamamoto

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2012

Login to get access

Abstract

Purpose

The pharmacokinetic (PK)–pharmacodynamic (PD) relationship of amrubicin and its active metabolite, amrubicinol, has only been evaluated using trough levels of these agents since the full PK profiles not yet been clarified so far. This study was performed to analyze the full PK profiles of amrubicin and amrubicinol and to evaluate their toxicity–PK relationships in Japanese patients.

Methods

Amrubicin (35–40 mg/m2) was administered to 21 lung cancer patients on days 1–3 every 3–4 weeks. Fourteen blood samples were obtained per patient over the course of 3 administration days. The plasma concentrations of amrubicin and amrubicinol were quantitated by HPLC, and the relationships between PK parameters of these compounds and hematological toxicities were evaluated.

Results

The overall PK profiles of amrubicin and amrubicinol were well characterized using a 3-compartment model and a 1-compartment model with a first-order metabolic process, respectively. The major toxicities were hematological. The clearance of amrubicinol was significantly correlated with grade 4 neutropenia (P = 0.01). The percentage decreases in the neutrophil count, hemoglobin level and platelet count were well correlated with the amrubicinol AUC.

Conclusion

The pharmacokinetic profiles of amrubicin and amrubicinol were clarified, and the subsequent PK–PD analyses indicate that the clearance of amrubicinol is the major determinant of neutropenia.
Literature
1.
Hanada M, Mizuno S, Fukushima A, Saito Y, Noguchi T, Yamaoka T (1998) A new antitumor agent amrubicin induces cell growth inhibition by stabilizing topoisomerase II-DNA complex. Jpn J Cancer Res 89:1229–1238PubMedCrossRef
2.
Onoda S, Masuda N, Seto T, Eguchi K, Takiguchi Y, Isobe H, Okamoto H, Ogura T, Yokoyama A, Seki N, Asaka-Amano Y, Harada M, Tagawa A, Kunikane H, Yokoba M, Uematsu K, Kuriyama T, Kuroiwa Y, Watanabe K (2006) Phase II trial of amrubicin for treatment of refractory or relapsed small-cell lung cancer: Thoracic Oncology Research Group Study 0301. J Clin Oncol 24:5448–5453PubMedCrossRef
3.
Kato T, Nokihara H, Ohe Y, Yamamoto N, Sekine I, Kunitoh H, Kubota K, Nishiwaki Y, Saijo N, Tamura T (2006) Phase II trial of amrubicin in patients with previously treated small cell lung cancer (SCLC) J Clin Oncol, ASCO Annual Meeting Proceedings Part I, (18S):7061
4.
Inoue A, Sugawara S, Yamazaki K, Maemondo M, Suzuki T, Gomi K, Takanashi S, Inoue C, Inage M, Yokouchi H, Watanabe H, Tsukamoto T, Saijo Y, Ishimoto O, Hommura F, Nukiwa T (2008) Randomized phase II trial comparing amrubicin with topotecan in patients with previously treated small-cell lung cancer: North Japan Lung Cancer Study Group Trial 0402. J Clin Oncol 26:5401–5406PubMedCrossRef
5.
Kaira K, Sunaga N, Tomizawa Y, Yanagitani N, Shimizu K, Imai H, Utsugi M, Iwasaki Y, Iijima H, Tsurumaki H, Yoshii A, Fueki N, Hisada T, Ishizuka T, Saito R, Mori M (2010) A phase II study of amrubicin, a synthetic 9-aminoanthracycline, in patients with previously treated lung cancer. Lung Cancer 69:99–104PubMedCrossRef
6.
Ettinger DS, Jotte R, Lorigan P, Gupta V, Garbo L, Alemany C, Conkling P, Spigel DR, Dudek AZ, Shah C, Salgia R, McNally R, Renschler MF, Oliver JW (2010) Phase II study of Amrubicin as second-line therapy in patients with platinum-refractory small-cell lung cancer. J Clin Oncol 28:2598–2603PubMedCrossRef
7.
Jotte R, Conkling P, Reynolds C, Galsky MD, Klein L, Fitzgibbons JF, McNally R, Renschler MF, Oliver JW (2011) Randomized phase II trial of single-agent amrubicin or topotecan as second-line treatment in patients with small-cell lung cancer sensitive to first-line platinum-based chemotherapy. J Clin Oncol 29:287–293PubMedCrossRef
8.
Kaneda H, Okamoto I, Hayashi H, Yoshioka H, Miyazaki M, Kudoh S, Kimura T, Sugiura T, Sawa T, Takeda K, Iwamoto Y, Satouchi M, Akita K, Saito H, Goto I, Shibata K, Fukuoka M, Nakagawa K (2010) Phase II trial of amrubicin for second-line treatment of advanced non-small cell lung cancer: results of the West Japan Thoracic Oncology Group trial (WJTOG0401). J Thorac Oncol 5:105–109PubMedCrossRef
9.
Matsunaga Y, Hamada A, Okamoto I, Sasaki J, Moriyama E, Kishi H, Matsumoto M, Hira A, Watanabe H, Saito H (2006) Pharmacokinetics of amrubicin and its active metabolite amrubicinol in lung cancer patients. Ther Drug Monit 28:76–82PubMedCrossRef
10.
Kimura T, Kudoh S, Mitsuoka S, Yoshimura N, Tanaka H, Asai K, Kyoh S, Tochino Y, Umekawa K, Hirata K (2009) Plasma concentration of amrubicinol in plateau phase in patients treated for 3 days with amrubicin is correlated with hematological toxicities. Anticancer Drugs 20:513–518PubMedCrossRef
11.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216PubMedCrossRef
12.
Ando R, Makino Y, Tamura T, Yamamoto N, Nishigaki R, Kimura T, Yokote N, Yamamoto H (2010) Simple and sensitive HPLC method for determination of amrubicin and amrubicinol in human plasma: application to a clinical pharmacokinetic study. Biomed Chromatogr 24:301–306PubMed
13.
Yamaoka T, Hanada M, Ichii S, Morisada S, Noguchi T, Yanagi Y (1998) Cytotoxicity of amrubicin, a novel 9-aminoanthracycline, and its active metabolite amrubicinol on human tumor cells. Jpn J Cancer Res 89:1067–1073PubMedCrossRef
14.
Vaidyanathan S, Boroujerdi M (2000) Interaction of dexrazoxane with red blood cells and hemoglobin alters pharmacokinetics of doxorubicin. Cancer Chemother Pharmacol 46:93–100PubMedCrossRef
15.
Tani N, Yabuki M, Komuro S, Kanamaru H (2005) Characterization of the enzymes involved in the in vitro metabolism of amrubicin hydrochloride. Xenobiotica 35:1121–1133PubMedCrossRef
16.
Lal S, Sandanaraj E, Wong ZW, Ang PC, Wong NS, Lee EJ, Chowbay B (2008) CBR1 and CBR3 pharmacogenetics and their influence on doxorubicin disposition in Asian breast cancer patients. Cancer Sci 99:2045–2054PubMedCrossRef
17.
Fan L, Goh BC, Wong CI, Sukri N, Lim SE, Tan SH, Guo JY, Lim R, Yap HL, Khoo YM, Iau P, Lee HS, Lee SC (2008) Genotype of human carbonyl reductase CBR3 correlates with doxorubicin disposition and toxicity. Pharmacogenet Genomics 18:621–631PubMedCrossRef
18.
Fleming RA, Drees J, Loggie BW, Russell GB, Geisinger KR, Morris RT, Sachs D, McQuellon RP (2002) Clinical significance of a NAD(P)H: quinone oxidoreductase 1 polymorphism in patients with disseminated peritoneal cancer receiving intraperitoneal hyperthermic chemotherapy with mitomycin C. Pharmacogenetics 12:31–37PubMedCrossRef
Metadata
Title
Pharmacokinetic and pharmacodynamic study on amrubicin and amrubicinol in Japanese patients with lung cancer
Authors
Yoshinori Makino
Noboru Yamamoto
Hitoshi Sato
Reiko Ando
Yasushi Goto
Chiharu Tanai
Hajime Asahina
Hiroshi Nokihara
Ikuo Sekine
Hideo Kunitoh
Yuichiro Ohe
Erika Sugiyama
Nobuaki Yokote
Tomohide Tamura
Hiroshi Yamamoto
Publication date
01-04-2012
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 4/2012
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-011-1768-8

Other articles of this Issue 4/2012

Cancer Chemotherapy and Pharmacology 4/2012 Go to the issue

Original Article

A novel multi-targeted tyrosine kinase inhibitor, linifanib (ABT-869), produces functional and structural changes in tumor vasculature in an orthotopic rat glioma model

Original Article

Evaluation of nilotinib in advanced GIST previously treated with imatinib and sunitinib

Original Article

Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers

Original Article

Influence of H2-receptor antagonists and proton pump inhibitors on dasatinib pharmacokinetics in Japanese leukemia patients

Original Article

A phase I dose-escalation and pharmacokinetic study of enzastaurin and erlotinib in patients with advanced solid tumors

Original Article

Differentiation-inducing factor-1 enhances 5-fluorouracil action on oral cancer cells inhibiting E2F1 and thymidylate synthase mRNAs accumulation
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