Safety, pharmacokinetics, and antiviral activity of AMD3100, a selective CXCR4 receptor inhibitor, in HIV-1 infection.
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.
Hendrix
Craig W
CW
Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. chendrix@jhmi.edu
Collier
Ann C
AC
Lederman
Michael M
MM
Schols
Dominique
D
Pollard
Richard B
RB
Brown
Stephen
S
Jackson
J Brooks
JB
Coombs
Robert W
RW
Glesby
Marshall J
MJ
Flexner
Charles W
CW
Bridger
Gary J
GJ
Badel
Karin
K
MacFarland
Ronald T
RT
Henson
Geoffrey W
GW
Calandra
Gary
G
D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001596:Benzylamines; D000080027:Cyclams; D004334:Drug Administration Schedule; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006571:Heterocyclic Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome
D019380:Anti-HIV Agents; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor