Pharmacodynamics, safety, and pharmacokinetics of BMS-663068, an oral HIV-1 attachment inhibitor in HIV-1-infected subjects.
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 log(10) 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. Clinical Trials Registration.NCT01009814.
Research and Development, Bristol-Myers Squibb (BMS), Princeton, New Jersey 08534, USA.
Richard E
RE
Nettles
Dirk
D
Schürmann
Li
L
Zhu
Michele
M
Stonier
Shu-Pang
SP
Huang
Ih
I
Chang
Caly
C
Chien
Mark
M
Krystal
Megan
M
Wind-Rotolo
Neelanjana
N
Ray
George J
GJ
Hanna
Richard
R
Bertz
Dennis
D
Grasela
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D004359:Drug Therapy, Combination; D005260:Female; D023581:HIV Fusion Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D010755:Organophosphates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D019438:Ritonavir / Q000627:therapeutic use; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects; D055815:Young Adult
D023581:HIV Fusion Inhibitors; D017320:HIV Protease Inhibitors; D010755:Organophosphates; D010879:Piperazines; D012367:RNA, Viral; C576364:fostemsavir; D019438:Ritonavir