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.

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

“…However, an unexpected rapid, transient leukocytosis was noticed during phase I/II clinical trials of AMD3100 in volunteers and HIV-infected patients, caused by the mobilization of various hematopoietic cells, including CD34-positive HSC, to the blood. 87,88 In the second trial in HIV patients, one patient receiving the highest dose of AMD3100 (160 mg/kg/h) had a significant drop in his viral load, but overall the efficacy of AMD3100 in affecting disease activity in HIV-1 patients was considered low and therefore this application was not further pursued for AMD3100. Instead, AnorMED explored AMD3100 as a mobilizing agent for HSC, 88 and a subsequent series of preclinical and clinical trials demonstrated that AMD3100 alone and in combination with G-CSF mobilizes HSC.…”

“…87,88 In the second trial in HIV patients, one patient receiving the highest dose of AMD3100 (160 mg/kg/h) had a significant drop in his viral load, but overall the efficacy of AMD3100 in affecting disease activity in HIV-1 patients was considered low and therefore this application was not further pursued for AMD3100. Instead, AnorMED explored AMD3100 as a mobilizing agent for HSC, 88 and a subsequent series of preclinical and clinical trials demonstrated that AMD3100 alone and in combination with G-CSF mobilizes HSC. 34,89,90 AMD3100 (recently re-named as Plerixafor or Mozobil) is now owned by Genzyme Corporation (Cambridge, MA, USA) after a recent takeover of AnorMED by Genzyme in late 2006.…”

“…More specific side effects are Plerixafor-related cardiac complications (premature ventricular contractions) in two patients treated with 40 and 160 mg/kg/h, who had a history of cardiac problems. 88 No cardiac side effects were reported for the subsequent clinical trials of Plerixafor for stem cell mobilization.…”

Rescue from failed growth factor and/or chemotherapy HSC mobilization with G-CSF and plerixafor (AMD3100): an institutional experience

“…During these trials, it was observed that plerixafor elicited a transient leukocytosis in healthy volunteers as well as HIV-1-infected individuals. 14,15 Subsequently, the role of plerixafor in the mobilization of PBSCs for auto-SCT was explored. 16,17 Plerixafor has been shown to rapidly increase circulating CD34 þ progenitor cells in preclinical murine models and healthy volunteers alone or in combination with G-CSF.…”

CXCR4, un récepteur de chimiokine aux multiples talents

“…On pouvait donc s'attendre à ce que le simple blocage, c'est-à-dire l'inhibition, de CXCR4 par des antirétroviraux donne lieu à des effets secondaires non acceptables, excluant l'utilisation à long terme d'antagonistes de CXCR4. L'effet le plus marqué de ce genre d'interventions thérapeutiques est la mobilisation de cellules souches hématopoïé-tiques de la moelle osseuse qui migrent alors dans la circulation sanguine [14]. Cet effet de mobilisation pourrait devenir intéressant pour des traitements de courte durée dans un contexte de greffe de cellules hématopoïétiques [15].…”