This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow An erratum has been published
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Stone, N. D.
Right arrow Articles by Hendrix, C. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Stone, N. D.
Right arrow Articles by Hendrix, C. W.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, July 2007, p. 2351-2358, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.00013-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Multiple-Dose Escalation Study of the Safety, Pharmacokinetics, and Biologic Activity of Oral AMD070, a Selective CXCR4 Receptor Inhibitor, in Human Subjects{triangledown} ,{dagger}

Nimalie D. Stone,1,{ddagger} Shelia B. Dunaway,2 Charles Flexner,1 Camlin Tierney,3 Gary B. Calandra,4 Stephen Becker,4 Ying-Jun Cao,1 Ilene P. Wiggins,1 Jeanne Conley,2 Ron T. MacFarland,4 Jeong-Gun Park,3 Christina Lalama,3 Sally Snyder,5 Beatrice Kallungal,5 Karin L. Klingman,6 and Craig W. Hendrix1*

Johns Hopkins University School of Medicine, Division of Clinical Pharmacology, Harvey 502, 600 N. Wolfe St., Baltimore, Maryland,1 University of Washington School of Medicine and Harborview Medical Center, 325 9th Avenue, Box 359929, Seattle, Washington 98104,2 Harvard School of Public Health, Boston, Massachusetts,3 AnorMED, Inc., 200-20353 64th Ave., Langley, British Columbia, Canada V2Y 1N55,4 Social and Scientific Systems, Inc., Silver Spring, Maryland,5 Division of AIDS, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland6

Received 5 January 2007/ Returned for modification 2 March 2007/ Accepted 9 April 2007

AMD070 is an oral CXCR4 antagonist with in vitro activity against X4-tropic human immunodeficiency virus type 1. Thirty fasting healthy male volunteers received oral doses of AMD070 ranging from a single 50-mg dose to seven 400-mg doses given every 12 h (q12h). Nine subjects received a 200-mg dose during fasting and prior to a meal. Subjects were monitored for safety and pharmacokinetics. AMD070 was well tolerated, without serious adverse events. Transient headaches (13 subjects) and neurocognitive (8 subjects) and gastrointestinal (7 subjects) symptoms were the most common complaints. Seven subjects had sinus tachycardia, and two were symptomatic. AMD070 plasma concentrations peaked 1 to 2 h after patient dosing. The estimated terminal half-life ranged from 11.2 to 15.9 h among cohorts. Dose proportionality was not demonstrated. Less than 1% of the drug appeared unchanged in the urine. Food reduced the maximum concentration of drug in serum and the area under the concentration-time curve from 0 to 24 h by 70% and 56%, respectively (P ≤ 0.01). A dose-dependent elevation of white blood cells (WBC) demonstrated a maximum twofold increase over baseline (95% confidence interval, 2.0- to 2.1-fold) in an Emax model. In healthy volunteers, AMD070 was well tolerated and demonstrated mixed-order pharmacokinetics, and food reduced drug exposure. AMD070 induced a dose-related elevation of WBC which was attributed to CXCR4 blockade. Using leukocytosis as a surrogate marker for CXCR4 inhibition, this dose-response relationship suggests that the doses used in this study were active in vivo, though not maximal, throughout the dosing interval. Trough concentrations with the 400-mg dose q12h exceeded the antiviral in vitro 90% effective concentration of AMD070.

* Corresponding author. Mailing address: Johns Hopkins University School of Medicine, Division of Clinical Pharmacology, Harvey 502, 600 N. Wolfe Street, Baltimore, MD 21287. Phone: (410) 955-9707. Fax: (410) 955-9708. E-mail: chendrix{at}jhmi.edu

{triangledown} Published ahead of print on 23 April 2007.

{dagger} This is ACTG Study A5191.

{ddagger} Present address: Emory University School of Medicine, Division of Infectious Diseases, Woodruff Memorial Building 2101, 1639 Pierce Dr., Atlanta, GA 30322.

Antimicrobial Agents and Chemotherapy, July 2007, p. 2351-2358, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.00013-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Murakami, T., Kumakura, S., Yamazaki, T., Tanaka, R., Hamatake, M., Okuma, K., Huang, W., Toma, J., Komano, J., Yanaka, M., Tanaka, Y., Yamamoto, N. (2009). The Novel CXCR4 Antagonist KRH-3955 Is an Orally Bioavailable and Extremely Potent Inhibitor of Human Immunodeficiency Virus Type 1 Infection: Comparative Studies with AMD3100. Antimicrob. Agents Chemother. 53: 2940-2948 [Abstract] [Full Text]  
  • Cao, Y. J., Flexner, C. W., Dunaway, S., Park, J.-G., Klingman, K., Wiggins, I., Conley, J., Radebaugh, C., Kashuba, A. D., MacFarland, R., Becker, S., Hendrix, C. W. (2008). Effect of Low-Dose Ritonavir on the Pharmacokinetics of the CXCR4 Antagonist AMD070 in Healthy Volunteers. Antimicrob. Agents Chemother. 52: 1630-1634 [Abstract] [Full Text]  
  • Moncunill, G., Armand-Ugon, M., Clotet-Codina, I., Pauls, E., Ballana, E., Llano, A., Romagnoli, B., Vrijbloed, J. W., Gombert, F. O., Clotet, B., De Marco, S., Este, J. A. (2008). Anti-HIV Activity and Resistance Profile of the CXC Chemokine Receptor 4 Antagonist POL3026. Mol. Pharmacol. 73: 1264-1273 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»