This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ratain, M. J. Articles by Lane, L. B. Search for Related Content PubMed PubMed Citation Articles by Ratain, M. J. Articles by Lane, L. B.

Phase I Study of Amonafide Dosing Based on Acetylator Phenotype¹

Section of Hematology/Oncology, Department of Medicine, Committee on Clinical Pharmacology, and the Cancer Research Center, University of Chicago Prizker School of Medicine, Chicago, Illinois 60637

Amonafide is extensively metabolized, including N-acetylation to an active metabolite. Prior studies have demonstrated that patients who are fast acetylators of amonafide (and other drugs) have increased toxicity at standard doses of amonafide. The primary objective of this study was to define the recommended phase II dose of amonafide separately for slow and fast acetylators. Twenty-six patients with advanced cancer underwent acetylator phenotyping with caffeine and were assigned to a dose level. Slow acetylators were treated at 375 mg/m² (daily for 5 days) and had a median WBC nadir of 1600/µl. Fast acetylators were treated at both 200 and 250 mg/m², resulting in median WBC nadirs of 5300 and 2000/µl, respectively. Two patients were not typeable, and two patients appear to have been misphenotyped, one in each phenotype category. Pharmacodynamic analysis yielded a model for nadir WBC including acetylator phenotype, 24-h N-acetyl-amonafide plasma concentration, gender, and pretreatment WBC. We recommend doses of 250 and 375 mg/m² (for 5 days) for further phase II testing of amonafide in fast and slow acetylators, respectively.

¹ Supported in part by N01-CM-07301 and CA14599.

² To whom requests for reprints should be addressed, at University of Chicago Medical Center, 5841 S. Maryland Avenue, MC2115, Chicago, IL 60637.

Received 11/ 5/92. Accepted 3/11/93.

This article has been cited by other articles:

				H. Zhu, M. Huang, F. Yang, Y. Chen, Z.-H. Miao, X.-H. Qian, Y.-F. Xu, Y.-X. Qin, H.-B. Luo, X. Shen, et al. R16, a novel amonafide analogue, induces apoptosis and G2-M arrest via poisoning topoisomerase II Mol. Cancer Ther., February 1, 2007; 6(2): 484 - 495. [Abstract] [Full Text] [PDF]

				M. J. Ratain, A. A. Miller, H. L. McLeod, A. P. Venook, M. J. Egorin, and R. L. Schilsky The cancer and leukemia group B pharmacology and experimental therapeutics committee: a historical perspective. Clin. Cancer Res., June 1, 2006; 12(11): 3612s - 3616s. [Abstract] [Full Text] [PDF]

				F. Innocenti, L. Iyer, and M. J. Ratain Pharmacogenetics of Anticancer Agents: Lessons from Amonafide and Irinotecan Drug Metab. Dispos., April 1, 2001; 29(4): 596 - 600. [Abstract] [Full Text]

				M. E. Costanza, R. B. Weiss, I. C. Henderson, L. Norton, D. A. Berry, C. Cirrincione, E. Winer, W. C. Wood, E. Frei III, O. R. McIntyre, et al. Safety and Efficacy of Using a Single Agent or a Phase II Agent Before Instituting Standard Combination Chemotherapy in Previously Untreated Metastatic Breast Cancer Patients: Report of a Randomized Study—Cancer and Leukemia Group B 8642 J. Clin. Oncol., May 1, 1999; 17(5): 1397 - 1397. [Abstract] [Full Text] [PDF]