Taking Darunavir/Cobicistat With Novel Attachment Inhibitor BMS-663068 Is Safe

Dosing darunavir/cobicistat (Prezcobix) with an investigational HIV attachment inhibitor did not have a meaningful clinical impact on concentrations of the attachment inhibitor, BMS-626529, in two studies of healthy volunteers. No serious adverse events developed in the 14-day studies.

BMS-663068 metabolizes to BMS-626529, a novel attachment inhibitor that binds directly to the HIV envelope protein gp120. A phase 2b trial found that BMS-663068 plus raltegravir (Isentress) and tenofovir (Viread) matched a ritonavir-boosted atazanavir (Reyataz) regimen in 48-week virologic response among people with antiretroviral experience.

Because cobicistat-boosted darunavir has been licensed for treatment-experienced patients, Bristol-Myers Squibb (BMS) investigators assessed the impact of darunavir/cobicistat and cobicistat alone (Tybost) on the pharmacokinetics of BMS-626529. The CYP3A pathway contributes to BMS-626529 metabolism, and cobicistat inhibits CYP3A.

This open-label, two-cohort study involved 32 healthy volunteers, with 16 assigned to each of two dosing sequences. Cohort 1 took 600 mg of BMS-663068 twice daily on days one through four then added standard-dose once-daily darunavir/cobicistat on days five through 14. Cohort 2 took 600 mg of BMS-663068 twice daily on days one through four than added 150 mg of cobicistat daily without darunavir on days five through 14. Researchers collected samples for up to 12 hours after the morning dose on days four and 14 to measure BMS-626529 area under the concentration-time curve (AUCtau), maximum concentration (Cmax) and 12-hour concentration (C12). They compared BMS-626529 concentrations alone and with darunavir/cobicistat and cobicistat alone by calculating geometric mean ratios (GMRs) from log-transformed data by mixed-effect modeling.

Volunteers had a median age of 40 years (range 25 to 50), two-thirds in each cohort were men, two-thirds white, and one-third African American. No one died during the study and no serious adverse events developed. Four volunteers (13%) dropped out of the study because of drug-related adverse events, including two cases of mild emesis, one moderate drug eruption and one case of mild pyrexia. Headache was the most frequent adverse event, affecting six participants (19%).

Adjusted GMRs indicated that darunavir/cobicistat boosted BMS-626529 AUCtau 97%, Cmax 79%, and C12 124% compared with BMS-663068 alone. Cobicistat alone raised BMS-626529 AUCtau 93%, Cmax 71%, and C12 136% compared with BMS-663068 alone. Because adjusted GMRs proved similar with darunavir/cobicistat and with cobicistat alone, the investigators propose that the impact of darunavir/cobicistat coadministration on systemic exposure of BMS-626529 probably reflects the effect of cobicistat.

The researchers conclude that these results, combined with data from previous studies, indicate that the approximately doubled exposure of BMS-626529 with darunavir/cobicistat "will not have a clinically meaningful effect on the safety or efficacy of BMS-663068." The BMS team proposes that no dose adjustment will be needed when BMS-663068 is given with cobicistat or darunavir/cobicistat.