title: Pharmacokinetics and safety of AMD-3100, a novel antagonist of the CXCR-4 chemokine receptor, in human volunteers.
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.
authors.affiliation: Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. chendrix@jhmi.com
authors.forename: C W
authors.initials: CW
authors.lastname: Hendrix
authors.forename: C
authors.initials: C
authors.lastname: Flexner
authors.forename: R T
authors.initials: RT
authors.lastname: MacFarland
authors.forename: C
authors.initials: C
authors.lastname: Giandomenico
authors.forename: E J
authors.initials: EJ
authors.lastname: Fuchs
authors.forename: E
authors.initials: E
authors.lastname: Redpath
authors.forename: G
authors.initials: G
authors.lastname: Bridger
authors.forename: G W
authors.initials: GW
authors.lastname: Henson
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D007279:Injections, Subcutaneous; D051379:Mice; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*
chemical_list: D019380:Anti-HIV Agents; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor