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

J Acquir Immune Defic Syndr. 2004 Oct 1;37(2):1253-62. doi: 10.1097/01.qai.0000137371.80695.ef.

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.

Publication types

  • Clinical Trial
  • Controlled Clinical Trial
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anti-HIV Agents / adverse effects
  • Anti-HIV Agents / pharmacokinetics
  • Anti-HIV Agents / therapeutic use*
  • Drug Administration Schedule
  • HIV Infections / drug therapy*
  • HIV Infections / metabolism
  • HIV-1 / drug effects
  • HIV-1 / genetics
  • HIV-1 / physiology
  • Heterocyclic Compounds / adverse effects
  • Heterocyclic Compounds / pharmacokinetics
  • Heterocyclic Compounds / therapeutic use*
  • Humans
  • Receptors, CXCR4 / antagonists & inhibitors*
  • Receptors, CXCR4 / metabolism
  • Treatment Outcome

Substances

  • Anti-HIV Agents
  • Heterocyclic Compounds
  • Receptors, CXCR4
  • plerixafor octahydrochloride