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

Abstract

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.

Pharmacokinetic Interactions between BMS-626529, the Active Moiety of the HIV-1 Attachment Inhibitor Prodrug BMS-663068, and Ritonavir or Ritonavir-Boosted Atazanavir in Healthy Subjects

“…(q12h) plus RTV at 100 mg q12h or every morning with those in subjects receiving BMS-663068 alone at 1,200 mg q12h (15). The moderate increase in BMS-626529 systemic exposure observed in the presence of RTV is consistent with the metabolic profile of the compound, in that RTV inhibits the CYP3A-mediated metabolism of BMS-626529 but has a minimal effect on the esterase-mediated hydrolysis pathway.…”

“…As both ATV and RTV are potent inhibitors of CYP3A4 (12,13), it was anticipated that coadministration of ATV and RTV with BMS-663068 could result in greater systemic exposures of BMS-626529. This is supported by results from earlyphase pharmacokinetic (PK) studies (14)(15)(16) that have shown that RTV moderately increases BMS-626529 systemic exposure. In contrast, as neither BMS-663068 nor BMS-626529 inhibits CYP3A4 in vitro, coadministration of BMS-663068 with RTV and/or ATV is not expected to affect RTV or ATV exposures.…”

Model-Based Phase 3 Dose Selection for HIV-1 Attachment Inhibitor Prodrug BMS-663068 in HIV-1-Infected Patients: Population Pharmacokinetics/Pharmacodynamics of the Active Moiety, BMS-626529

“…Baseline viral drug susceptibility appeared to be the most influential factor in determining the magnitude of the decline in HIV-1 RNA levels during BMS-663068 monotherapy, in line with observations from the AI438006 study (6,10), and the most compelling exposure-response relationships were observed with log etransformed PBAIC 50 -adjusted C ss,avg and C tau . There were no significant differences between the C ss,avg and C tau models, so, as C tau is generally considered to be a better predictor of antiviral activity, the C tau model was selected for the modeling and simulation analysis.…”

“…Only subjects with a baseline BMS-626529 half-maximal (50%) inhibitory concentration (IC 50 ) of Ͻ100 nM were included in the AI438011 study (7); the baseline BMS-626529 IC 50 was not an exclusion criterion for the AI438006 study. Plasma samples were analyzed for BMS-626529 concentrations by a validated liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) assay as previously described (6).…”

“…In a phase 2a study of BMS-663068 monotherapy with or without RTV boosting in treatment-naive and treatment-experienced subjects (AI438006 study; ClinicalTrials.gov registration num-ber NCT01009814), a maximum median decline in the plasma HIV-1 RNA level of 1.12 to 1.73 log 10 copies/ml was observed after 8 days of treatment (6). The greatest virologic response (a change in the HIV-1 RNA level from the baseline level of Ն1 log 10 copies/ ml) to BMS-663068 treatment was in subjects with a baseline BMS-626529 half-maximal (50%) inhibitory concentration (IC 50 ) of Յ100 nM, with no change in efficacy detected across a wide range of doses.…”