Pharmacodynamics, Safety, and Pharmacokinetics of BMS-663068, an Oral HIV-1 Attachment Inhibitor in HIV-1-Infected Subjects

• Published in: The Journal of infectious diseases Vol. 206; no. 7; pp. 1002 - 1011
• Main Authors: Nettles, Richard E., Schürmann, Dirk, Zhu, Li, Stonier, Michele, Huang, Shu-Pang, Chang, Ih, Chien, Caly, Krystal, Mark, Wind-Rotolo, Megan, Ray, Neelanjana, Hanna, George J., Bertz, Richard, Grasela, Dennis
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.10.2012
• Subjects: Adult; Aged; Antiretrovirals; Antivirals; Area Under Curve; Biological and medical sciences; Dosage; Drug Therapy, Combination; Female; Fundamental and applied biological sciences. Psychology; Health care administration; HIV 1; HIV Fusion Inhibitors - adverse effects; HIV Fusion Inhibitors - pharmacokinetics; HIV Fusion Inhibitors - therapeutic use; HIV Infections - blood; HIV Infections - drug therapy; HIV Infections - virology; HIV Protease Inhibitors - therapeutic use; HIV-1 - drug effects; HIV-1 - genetics; HIV/AIDS; Human immunodeficiency virus 1; Human viral diseases; Humans; Infectious diseases; Inhibitory Concentration 50; Male; Medical sciences; Microbiology; Middle Aged; Miscellaneous; Organophosphates - adverse effects; Organophosphates - pharmacokinetics; Organophosphates - therapeutic use; Pharmacokinetics; Piperazines - adverse effects; Piperazines - pharmacokinetics; Piperazines - therapeutic use; Ritonavir - therapeutic use; RNA; RNA, Viral - blood; T lymphocytes; Treatment Outcome; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Viral Load - drug effects; Virology; Viruses; Young Adult; Virus; Infection; Immunopathology; HIV-1 virus; Viral disease; Retroviridae; AIDS; Human immunodeficiency virus; Immune deficiency; Lentivirus
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1093/infdis/jis432

Background. BMS-663068 is a prodrug of the small-molecule inhibitor BMS-626529, which inhibits human immunodeficiency virus type 1 (HIV-1) infection by binding to gp120 and interfering with the attachment of virus to CD4+ T-cells. Methods. Fifty HIV-1-infected subjects were randomized to 1 of 5 regimen groups (600 mg BMS-663068 plus 100 mg ritonavir every 12 hours [Q12H], 1200 mg BMS-663068 plus 100 mg ritonavir every bedtime, 1200 mg BMS-663068 plus 100 mg ritonavir Q12H, 1200 mg BMS-663068 Q12H plus 100 mg ritonavir every morning, or 1200 mg BMS-663068 Q12H) for 8 days in this open-label, multiple-dose, parallel study. The study assessed the pharmacodynamics, pharmacokinetics, and safety of BMS-663068. Results. The maximum median decrease in plasma HIV-1 RNA load from baseline ranged from 1.21 to 1.73 log₁₀ copies/mL. Plasma concentrations of BMS-626529 were not associated with an antiviral response, while low baseline inhibitory concentrations and the minimum and average steady-state BMS-626529 plasma concentrations, when adjusted by the baseline protein binding-adjusted 90% inhibitory concentration (inhibitory quotient), were linked with antiviral response. BMS-663068 was generally well tolerated. Conclusions. Administration of BMS-663068 for 8 days with or without ritonavir resulted in substantial declines in plasma HIV-1 RNA levels and was generally well tolerated. Longer-term clinical trials of BMS-663068 as part of combination antiretroviral therapy are warranted.