TY - JOUR
T1 - Pharmacokinetics and safety of AMD-3100, a novel antagonist of the CXCR- 4 chemokine receptor, in human volunteers
AU - Hendrix, Craig W.
AU - Flexner, Charles
AU - Macfarland, Ronald T.
AU - Giandomenico, Christen
AU - Fuchs, Edward J.
AU - Redpath, Ella
AU - Bridger, Gary
AU - Henson, Geoffrey W.
PY - 2000
Y1 - 2000
N2 - 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 μg/kg. Five subjects also received a single subcutaneous injection of AMD-3100 (40 or 80 μg/kg). Three subjects received two escalating oral doses each (80 and 160 μg/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 ∞ (AUC(0-∞)) over the entire dose range. At the highest intravenous dose (80 μg/kg), the median C(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 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.
AB - 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 μg/kg. Five subjects also received a single subcutaneous injection of AMD-3100 (40 or 80 μg/kg). Three subjects received two escalating oral doses each (80 and 160 μg/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 ∞ (AUC(0-∞)) over the entire dose range. At the highest intravenous dose (80 μg/kg), the median C(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 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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U2 - 10.1128/AAC.44.6.1667-1673.2000
DO - 10.1128/AAC.44.6.1667-1673.2000
M3 - Article
C2 - 10817726
AN - SCOPUS:0034120373
SN - 0066-4804
VL - 44
SP - 1667
EP - 1673
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 6
ER -