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Safety, pharmacokinetics, and antiviral activity of AMD3100, a selective CXCR4 receptor inhibitor, in HIV-1 infection.

Abstract
AMD3100 is a CXCR4 receptor inhibitor with anti-HIV-1 activity in vitro. We tested the safety, pharmacokinetics, and antiviral effect of AMD3100 administered for 10 days by continuous intravenous infusion in an open-label dose escalation study from 2.5 to 160 microg/kg/h. Forty HIV-infected patients with an HIV RNA level >5000 copies/mL on stable antiretroviral (ARV) regimens or off therapy were enrolled. Syncytium-inducing (SI) phenotype in an MT-2 cell assay was required in higher dose cohorts. Most subjects were black (55%), male (98%), and off ARV therapy. HIV phenotype was SI (30%), non-SI (45%), or not tested (25%). One patient (5 microg/kg/h) had serious and possibly drug-related thrombocytopenia. Two patients (40 and 160 microg/kg/h) had unexpected, although not serious, premature ventricular contractions. Most patients in the 80- and 160-microg/kg/h cohorts had paresthesias. Steady-state blood concentration and area under the concentration-time curve were dose proportional across all dose levels; the median terminal elimination half-life was 8.6 hours (range: 8.1-11.1 hours). Leukocytosis was observed in all patients, with an estimated maximum effect of 3.4 times baseline (95% confidence interval: 2.9-3.9). Only 1 patient, the patient whose virus was confirmed to use purely CXCR4 and who also received the highest dose (160 microg/kg/h), had a significant 0.9-log10 copies/mL HIV RNA drop at day 11. Overall, however, the average change in viral load across all patients was +0.03 log10 HIV RNA. Given these results, AMD3100 is not being further developed for ARV therapy, but development continues for stem cell mobilization.
AuthorsCraig W Hendrix, Ann C Collier, Michael M Lederman, Dominique Schols, Richard B Pollard, Stephen Brown, J Brooks Jackson, Robert W Coombs, Marshall J Glesby, Charles W Flexner, Gary J Bridger, Karin Badel, Ronald T MacFarland, Geoffrey W Henson, Gary Calandra, AMD3100 HIV Study Group
JournalJournal of acquired immune deficiency syndromes (1999) (J Acquir Immune Defic Syndr) Vol. 37 Issue 2 Pg. 1253-62 (Oct 01 2004) ISSN: 1525-4135 [Print] United States
PMID15385732 (Publication Type: Clinical Trial, Controlled Clinical Trial, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Anti-HIV Agents
  • Benzylamines
  • Cyclams
  • Heterocyclic Compounds
  • Receptors, CXCR4
  • plerixafor
Topics
  • Anti-HIV Agents (adverse effects, pharmacokinetics, therapeutic use)
  • Benzylamines
  • Cyclams
  • Drug Administration Schedule
  • HIV Infections (drug therapy, metabolism)
  • HIV-1 (drug effects, genetics, physiology)
  • Heterocyclic Compounds (adverse effects, pharmacokinetics, therapeutic use)
  • Humans
  • Receptors, CXCR4 (antagonists & inhibitors, metabolism)
  • Treatment Outcome

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