Proof of Activity with AMD11070, an Orally Bioavailable Inhibitor of CXCR4‐Tropic HIV Type 1

Moyle, Graeme; DeJesus, Edwin; Boffito, Marta; Wong, Rebecca S.Y.; Gibney, Colleen; Badel, Karin; MacFarland, Ron; Calandra, Gary B.; Bridger, Gary; Becker, Stephen; Team, X Antagonist Concept Trial Study

doi:10.1086/597097

Cited by 73 publications

(55 citation statements)

References 28 publications

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“…A majority of the subjects dosed with 200 mg twice daily attained plasma concentrations at or near the in vitro 90% effective concentration 24 h after dosing. The combined results of two related 10-day phase II studies of HIV-infected subjects receiving 200 mg AMD070 twice daily demonstrated an antiviral effect, defined as a 1-log reduction in X4 relative luminescence units in the profile assay, in 7 of 15 subjects (13,17). Furthermore, like its predecessor, AMD3100, AMD070 showed a dose response for leukocytosis which may serve as a surrogate marker for CXCR4 inhibition and a second potential indication for use of the drug.…”

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confidence: 98%

Effect of Low-Dose Ritonavir on the Pharmacokinetics of the CXCR4 Antagonist AMD070 in Healthy Volunteers

Cao

Flexner

Dunaway

et al. 2008

Antimicrob Agents Chemother

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AMD070, a CXCR4 antagonist, has demonstrated antiretroviral activity in human immunodeficiency virusinfected 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 ⅐ ng/ml (313 to 2,127 h ⅐ ng/ml) for the area under the concentration-time curve from 0 h to infinity (AUC 0-ؕ ), 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-ؕ 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.Despite the availability of many effective antiretroviral drugs, treatment options are still challenged by drug toxicities and the emergence of drug-resistant human immunodeficiency virus (HIV). The identification of a new class of drugs with a novel mechanism of action, durable efficacy, and lack of crossresistance with existing antiretroviral drug classes remains a continuing therapeutic need. AMD070 belongs to a novel class of antiretroviral entry inhibitors (AnorMED, Inc., data on file). It is a specific and reversible antagonist of the CXCR4 chemokine receptor, the coreceptor used by T-cell tropic (X4), syncytium-inducing HIVs, and has a potent and selective ability in vitro to inhibit X4 viral replication by blocking fusion and viral entry into the cell. The investigational CXCR4 antagonist AMD3100 given intravenously has been shown to reduce the X4 viral load in HIV-infected subjects; however, its development for HIV infection was terminated due to poor oral bioavailability and adverse effects (7,8). AMD3100 is currently in phase III clinical trials as an intravenous adjunct for stem cell mobilization in malignant diseases. In contrast, orally administered AMD070 is well absorbed and well tolerated and displays a terminal elimination half-life of 11 to 16 h (19). A majority of the subjects dosed with 200 mg twice daily attained plasma concentrations at or near the in vitr...

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confidence: 98%

Effect of Low-Dose Ritonavir on the Pharmacokinetics of the CXCR4 Antagonist AMD070 in Healthy Volunteers

Cao

Flexner

Dunaway

et al. 2008

Antimicrob Agents Chemother

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“…Proof of concept that AMD070 (originally referred to as AMD11070) can selectively inhibit X4-tropic virus in HIV-1-infected patients was provided by Saag and colleagues [54] and Moyle and colleagues [55]. Like AMD3100, AMD070 induced a dose-related elevation of the WBC counts, which can be attributed to CXCR4 blockade.…”

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The AMD3100 story: The path to the discovery of a stem cell mobilizer (Mozobil)

Clercq

2009

Biochemical Pharmacology

254

212

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“…AMD070 (also known as AMD11070), which has two aromatic rings in addition to a primary and a tertiary amine, has an IC 50 of 2 to 26 nM against an X4 HIV strain and is orally bioavailable (22,29).…”

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Novel Compounds Containing Multiple Guanide Groups That Bind the HIV Coreceptor CXCR4

Wilkinson

Pincus

Shepard

et al. 2011

Antimicrob Agents Chemother

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The G-protein-coupled receptor CXCR4 acts as a coreceptor for human immunodeficiency virus type 1 (HIV-1) infection, as well as being involved in signaling cell migration and proliferation. Compounds that block CXCR4 interactions have potential uses as HIV entry inhibitors to complement drugs such as maraviroc that block the alternate coreceptor CCR5 or in cancer therapy. The peptide T140, which contains five arginine residues, is the most potent antagonist of CXCR4 developed to date. In a search for nonpeptide CXCR4 ligands that could inhibit HIV entry, three series of compounds were synthesized from 12 linear and branched polyamines with 2, 3, 4, 6, or 8 amino groups, which were substituted to produce the corresponding guanidines, biguanides, or phenylguanides. The resulting compounds were tested for their ability to compete with T140 for binding to the human CXCR4 receptor expressed on mammalian cells. The most effective compounds bound CXCR4 with a 50% inhibitory concentration of 200 nM, and all of the compounds had very low cytotoxicity. Two series of compounds were then tested for their ability to inhibit the infection of TZM-bl cells with X4 and R5 strains of HIV-1. Spermine phenylguanide and spermidine phenylguanide inhibited infection by X4 strains, but not by R5 strains, at low micromolar concentrations. These results support further investigation and development of these compounds as HIV entry inhibitors.

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Proof of Activity with AMD11070, an Orally Bioavailable Inhibitor of CXCR4‐Tropic HIV Type 1

Cited by 73 publications

References 28 publications

Effect of Low-Dose Ritonavir on the Pharmacokinetics of the CXCR4 Antagonist AMD070 in Healthy Volunteers

Effect of Low-Dose Ritonavir on the Pharmacokinetics of the CXCR4 Antagonist AMD070 in Healthy Volunteers

The AMD3100 story: The path to the discovery of a stem cell mobilizer (Mozobil)

Novel Compounds Containing Multiple Guanide Groups That Bind the HIV Coreceptor CXCR4

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