title: Multiple-dose escalation study of the safety, pharmacokinetics, and biologic activity of oral AMD070, a selective CXCR4 receptor inhibitor, in human subjects.
abstract: 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 < or = 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 E(max) 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.
authors: Johns Hopkins University School of Medicine, Division of Clinical Pharmacology, Harvey 502, 600 N. Wolfe Street, Baltimore, MD 21287, USA.
authors: Nimalie D
authors: ND
authors: Stone
authors: Shelia B
authors: SB
authors: Dunaway
authors: Charles
authors: C
authors: Flexner
authors: Camlin
authors: C
authors: Tierney
authors: Gary B
authors: GB
authors: Calandra
authors: Stephen
authors: S
authors: Becker
authors: Ying-Jun
authors: YJ
authors: Cao
authors: Ilene P
authors: IP
authors: Wiggins
authors: Jeanne
authors: J
authors: Conley
authors: Ron T
authors: RT
authors: MacFarland
authors: Jeong-Gun
authors: JG
authors: Park
authors: Christina
authors: C
authors: Lalama
authors: Sally
authors: S
authors: Snyder
authors: Beatrice
authors: B
authors: Kallungal
authors: Karin L
authors: KL
authors: Klingman
authors: Craig W
authors: CW
authors: Hendrix
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000634:Aminoquinolines; D019540:Area Under Curve; D001562:Benzimidazoles; D002082:Butylamines; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005215:Fasting; D006207:Half-Life; D006261:Headache / Q000139:chemically induced; D006573:Heterocyclic Compounds, 1-Ring / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006801:Humans; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D013997:Time Factors
chemical_list: D000634:Aminoquinolines; D001562:Benzimidazoles; D002082:Butylamines; D006573:Heterocyclic Compounds, 1-Ring; D019718:Receptors, CXCR4; C494414:mavorixafor