Pharmacokinetics and Safety of AMD-3100, a Novel Antagonist of the CXCR-4 Chemokine Receptor, in Human Volunteers

doi:10.1128/AAC.44.6.1667-1673.2000

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Antimicrobial Agents and Chemotherapy, June 2000, p. 1667-1673, Vol. 44, No. 6
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Pharmacokinetics and Safety of AMD-3100, a Novel Antagonist of the CXCR-4 Chemokine Receptor, in Human Volunteers

Craig W. Hendrix,¹^,^* Charles Flexner,¹ Ronald T. MacFarland,² Christen Giandomenico,² Edward J. Fuchs,¹ Ella Redpath,¹ Gary Bridger,² and Geoffrey W. Henson²

Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287,¹ and AnorMED, Inc., Langley, British Columbia, Canada V2Y 1N5²

Received 9 August 1999/Returned for modification 15 January 2000/Accepted 18 March 2000

AMD-3100, a bicyclam, is a novel agent that uniquely inhibits the entry of human immunodeficiency virus type 1 (HIV-1) intoCD4⁺ T cells via selective blockade of the chemokine CXCR-4 receptor.Twelve healthy volunteers were given AMD-3100 as a single 15-minintravenous infusion at 10, 20, 40, or 80 µg/kg. Five subjectsalso received a single subcutaneous injection of AMD-3100 (40or 80 µg/kg). Three subjects received two escalating oral doseseach (80 and 160 µg/kg). All subjects tolerated their dose(s)well without any grade 2 toxicity or dose adjustment. Six subjectsexperienced mild, transient symptoms, primarily gastrointestinalin nature and not dose related. All subjects experienced a dose-relatedelevation of the white blood cell count, from 1.5 to 3.1 timesthe baseline, which returned to the baseline 24 h after dosing.AMD-3100 demonstrated dose proportionality for the maximum drugconcentration in serum (C_max) and the area under the concentration-timecurve from 0 h to $infinity$ (AUC_0-) over the entire doserange. At the highest intravenous dose (80 µg/kg), the medianC_max was 515 (range, 470 to 521) ng/ml and the AUC_0-was 1,044 (range, 980 to 1,403) ng-h/ml. The median systemic absorptionafter subcutaneous dosing was 87% (range, 67 to 106%). No drugwas detectable in the blood following oral dosing. Using a two-compartmentmodel, the median pharmacokinetic parameter estimates (ranges)were as follows: volume of distribution, 0.34 (0.27 to 0.36) liter/kg;clearance, 1.30 (0.97 to 1.34) liters/h; elimination half-life,3.6 (3.5 to 4.9) h. After a single, well-tolerated intravenousdose of AMD-3100, concentrations were sustained for 12 h abovethe in vitro antiretroviral 90% inhibitory concentrations andfor 8 h above antiviral concentrations identified in the SCID-huThy/Liv mouse model of HIVinfection.

^* Corresponding author. Mailing address: Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Harvey502, 600 N. Wolfe St., Baltimore, MD 21287. Phone: (410) 955-9707.Fax: (410) 955-9708. E-mail: chendrix{at}jhmi.com.

Antimicrobial Agents and Chemotherapy, June 2000, p. 1667-1673, Vol. 44, No. 6
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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