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Link to original content: https://pubmed.ncbi.nlm.nih.gov/10817726/
Pharmacokinetics and safety of AMD-3100, a novel antagonist of the CXCR-4 chemokine receptor, in human volunteers - PubMed Skip to main page content
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Clinical Trial
. 2000 Jun;44(6):1667-73.
doi: 10.1128/AAC.44.6.1667-1673.2000.

Pharmacokinetics and safety of AMD-3100, a novel antagonist of the CXCR-4 chemokine receptor, in human volunteers

C W Hendrix  1 , C Flexner, R T MacFarland, C Giandomenico, E J Fuchs, E Redpath, G Bridger, G W Henson
Affiliations
Clinical Trial

Pharmacokinetics and safety of AMD-3100, a novel antagonist of the CXCR-4 chemokine receptor, in human volunteers

C W Hendrix et al. Antimicrob Agents Chemother. 2000 Jun.

Abstract

AMD-3100, a bicyclam, is a novel agent that uniquely inhibits the entry of human immunodeficiency virus type 1 (HIV-1) into CD4(+) T cells via selective blockade of the chemokine CXCR-4 receptor. Twelve healthy volunteers were given AMD-3100 as a single 15-min intravenous infusion at 10, 20, 40, or 80 microg/kg. Five subjects also received a single subcutaneous injection of AMD-3100 (40 or 80 microg/kg). Three subjects received two escalating oral doses each (80 and 160 microg/kg). All subjects tolerated their dose(s) well without any grade 2 toxicity or dose adjustment. Six subjects experienced mild, transient symptoms, primarily gastrointestinal in nature and not dose related. All subjects experienced a dose-related elevation of the white blood cell count, from 1.5 to 3.1 times the baseline, which returned to the baseline 24 h after dosing. AMD-3100 demonstrated dose proportionality for the maximum drug concentration in serum (C(max)) and the area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)) over the entire dose range. At the highest intravenous dose (80 microg/kg), the median C(max) was 515 (range, 470 to 521) ng/ml and the AUC(0-infinity) was 1,044 (range, 980 to 1,403) ng-h/ml. The median systemic absorption after subcutaneous dosing was 87% (range, 67 to 106%). No drug was detectable in the blood following oral dosing. Using a two-compartment model, 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 intravenous dose of AMD-3100, concentrations were sustained for 12 h above the in vitro antiretroviral 90% inhibitory concentrations and for 8 h above antiviral concentrations identified in the SCID-hu Thy/Liv mouse model of HIV infection.

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Figures

FIG. 1
FIG. 1
Structure of AMD-3100, 1,1′-[1,4-phenylenebis(methylene)]-bis-1,4,8,11-azatetradecane.
FIG. 2
FIG. 2
WBC ratio versus time compared to AMD-3100 concentration versus time. Each line represents a different AMD-3100 dose cohort given 10 to 80 μg/kg by a short intravenous infusion. The WBC ratio is calculated as the ratio of WBC count at a given time to the predose WBC count. All values are displayed as the mean ± the standard deviation.
FIG. 3
FIG. 3
AMD-3100 concentration versus time (log10) following a 15-min intravenous infusion at four dose levels. The inset shows the linear concentration-versus-time curve. All values are the mean ± the standard deviation.
FIG. 4
FIG. 4
Dose proportionality of AMD-3100 pharmacokinetics (AUC0–∞ [AUCinf] and Cmax) across the four intravenous dose levels studied. The solid and dotted lines represent the mean and 95% confidence intervals, respectively, for the ordinary least-squares linear regression.
See this image and copyright information in PMC

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