Article

Effect of low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist AMD070 in healthy volunteers.

Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.45). 06/2008; 52(5):1630-4. DOI: 10.1128/AAC.01460-07
Source: PubMed

ABSTRACT AMD070, a CXCR4 antagonist, has demonstrated antiretroviral activity in human immunodeficiency virus-infected patients. Since AMD070 is a substrate of cytochrome P450 3A4 and P-glycoprotein, both of which may be affected by ritonavir, we tested for a ritonavir effect on AMD070 pharmacokinetics. Subjects were given a single 200-mg dose of AMD070 on days 1, 3, and 17. Ritonavir (100 mg every 12 h) was dosed from day 3 to day 18. Blood samples to test for AMD070 concentrations were collected over 48 h after each administration of AMD070. Twenty-three male subjects were recruited. Among them, 21 completed the study, and 2 were discontinued for reasons other than safety. All adverse events were grade 2 or lower. AMD070 alone had the following pharmacokinetic features, given as medians (ranges): 3 h (0.5 to 4 h) for the time to peak blood concentration, 256 ng/ml (41 to 845 ng/ml) for the peak concentration (C(max)), 934 h x ng/ml (313 to 2,127 h x ng/ml) for the area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)), 214 liters/h (94 to 639 liters/h) for apparent body clearance, and 4,201 liters (1,996 to 9,991 liters) for the apparent volume of distribution based on the terminal phase. The initial doses of ritonavir increased the C(max) of AMD070 [geometric mean (90% confidence interval)] by 39% (3 to 89%) and the AUC(0-infinity) by 60% (29 to 100%). After 14 days of ritonavir dosing, the pharmacokinetic changes in AMD070 persisted. The plasma pharmacokinetics of ritonavir were consistent with previous reports. It is concluded that AMD070 concentrations were increased with concomitant ritonavir dosing for 14 days in healthy volunteers.

1 Follower
 · 
93 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The chemokine CXCR4 receptor is a G-protein-coupled receptor that has multiple functions in normal physiologies involving the hematopoietic and immune systems. Although the CXCR4 receptor was initially discovered as one of the co-receptors involved in human immune deficiency virus (HIV) cell entry, it has also been linked to many central immune system functions through the direct regulation of cell trafficking and adhesion, and is present in many cell types within the body. The receptor ligand combination of CXCL12 (SDF-1) and CXCR4 underlies pathologies such as HIV infection, cancer metastasis and drug resistance, leukemia progression, rheumatoid arthritis, and lupus. This alternative and widespread functionality has allowed researchers to discover new potential uses for substances that are CXCR4 antagonists. This has resulted in approval of the first CXCR4 antagonist, plerixafor injection (AMD3100), for hematopoietic stem cell mobilization. Newer agents are under clinical evaluation for HIV, cancer, and stem cell mobilization. As these agents are further investigated, new uses and therapeutic interventions for CXCR4 antagonists will be discovered. Drug Dev Res 72:598–602, 2011. © 2011 Wiley Periodicals, Inc.
    Drug Development Research 11/2011; 72(7). DOI:10.1002/ddr.20469 · 0.73 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Entry of human immunodeficiency virus type 1 (HIV-1) into cells is mediated by attachment of the envelope glycoproteins, gp120 and gp41, to the CD4 receptor and a chemokine receptor (CCR5 or CXCR4) and subsequent fusion of viral and cellular membranes. Several steps of the entry process can be targeted by drugs. Receptor antagonists prevent virus attachment and fusion inhibitors block conformational changes that are required for membrane fusion. The T20 peptide (Enfuvirtide, Fuzeon), which is homologous to part of the gp41-encoded fusion machinery, is the only clinically approved fusion inhibitor, but over the last decade new generations of T20-like peptides have been developed with improved potency and stability, as well as fusion inhibitors that target alternative gp41 domains. Here, we will review the field of HIV-1 fusion inhibitors.
    02/2012; 2(1):50-9. DOI:10.1016/j.coviro.2012.01.002
  • [Show abstract] [Hide abstract]
    ABSTRACT: A de novo hit-to-lead effort involving the redesign of benzimidazole-containing antagonists of the CXCR4 receptor resulted in the discovery of a novel series of 1,2,3,4-tetrahydroisoquinoline (TIQ) analogues. In general, this series of compounds show good potencies (3-650 nM) in assays involving CXCR4 function, including both inhibition of attachment of X4 HIV-1IIIB virus in MAGI-CCR5/CXCR4 cells and inhibition of calcium release in Chem-1 cells. Series profiling permitted the identification of TIQ-(R)-stereoisomer 15 as a potent and selective CXCR4 antagonist lead candidate with a promising in vitro profile. The drug-like properties of 15 were determined in ADME in vitro studies, revealing low metabolic liability potential. Further in vivo evaluations included pharmacokinetic experiments in rats and mice, where 15 was shown to have oral bioavailability (F = 63%) and resulted in the mobilization of white blood cells (WBCs) in a dose-dependent manner.
    ACS Medicinal Chemistry Letters 11/2013; 4(11):1025-30. DOI:10.1021/ml400183q · 3.07 Impact Factor

Preview

Download
0 Downloads
Available from