title: 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.
abstract: BMS-663068 is a prodrug of BMS-626529, a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4(+) T cells. This open-label, multiple-dose, four-sequence, crossover study addressed potential two-way drug-drug interactions following coadministration of BMS-663068 (BMS-626529 is a CYP3A4 substrate), atazanavir (ATV), and ritonavir (RTV) (ATV and RTV are CYP3A4 inhibitors). Thirty-six healthy subjects were randomized 1:1:1:1 to receive one of four treatment sequences with three consecutive treatments: BMS-663068 at 600 mg twice daily (BID), BMS-663068 at 600 mg BID plus RTV at 100 mg once daily (QD), ATV at 300 mg QD plus RTV at 100 mg QD (RTV-boosted ATV [ATV/r]), or BMS-663068 at 600 mg BID plus ATV at 300 mg QD plus RTV at 100 mg QD. Compared with the results obtained by administration of BMS-663068 alone, coadministration of BMS-663068 with ATV/r increased the BMS-626529 maximum concentration in plasma (Cmax) and the area under the concentration-time curve in one dosing interval (AUCtau) by 68% and 54%, respectively. Similarly, coadministration of BMS-663068 with RTV increased the BMS-626529 Cmax and AUCtau by 53% and 45%, respectively. Compared with the results obtained by administration of ATV/r alone, ATV and RTV systemic exposures remained similar following coadministration of BMS-663068 with ATV/r. BMS-663068 was generally well tolerated, and there were no adverse events (AEs) leading to discontinuation, serious AEs, or deaths. Moderate increases in BMS-626529 systemic exposure were observed following coadministration of BMS-663068 with ATV/r or RTV. However, the addition of ATV to BMS-663068 plus RTV did not further increase BMS-626529 systemic exposure. ATV and RTV exposures remained similar following coadministration of BMS-663068 with either ATV/r or RTV. BMS-663068 was generally well tolerated alone or in combination with either RTV or ATV/r.
authors: Bristol-Myers Squibb, Research and Development, Princeton, New Jersey, USA li.zhu@bms.com.
authors: Li
authors: L
authors: Zhu
authors: Bristol-Myers Squibb, Research and Development, Princeton, New Jersey, USA.
authors: Matthew
authors: M
authors: Hruska
authors: Bristol-Myers Squibb, Research and Development, Princeton, New Jersey, USA.
authors: Carey
authors: C
authors: Hwang
authors: Bristol-Myers Squibb, Research and Development, Princeton, New Jersey, USA.
authors: Vaishali
authors: V
authors: Shah
authors: Bristol-Myers Squibb, Research and Development, Princeton, New Jersey, USA.
authors: Michael
authors: M
authors: Furlong
authors: Bristol-Myers Squibb, Research and Development, Princeton, New Jersey, USA.
authors: George J
authors: GJ
authors: Hanna
authors: Bristol-Myers Squibb, Research and Development, Princeton, New Jersey, USA.
authors: Richard
authors: R
authors: Bertz
authors: Bristol-Myers Squibb, Research and Development, Princeton, New Jersey, USA.
authors: Ishani Savant
authors: IS
authors: Landry
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000069446:Atazanavir Sulfate / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D010755:Organophosphates / Q000627:therapeutic use; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019438:Ritonavir / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014230:Triazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; C584152:BMS-626529; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D010755:Organophosphates; D010879:Piperazines; D014230:Triazoles; C514793:gp120 protein, Human immunodeficiency virus 1; D000069446:Atazanavir Sulfate; C576364:fostemsavir; D019438:Ritonavir