title: Enabled clinical use of an HIV-1 attachment inhibitor through drug delivery.
abstract: The clinical advancement of HIV-1 attachment inhibitors was hindered initially by poor bioavailability. Attempts to identify improved candidates revealed that solubility and dissolution-rate-limited absorption are barriers to achieving adequate antiviral plasma levels. This was mitigated by forming nanosized drugs or by creating stabilised amorphous drug-polymer composites. In further improving drug potency and mitigating solubility-limited bioavailability, a candidate based on a phosphate ester prodrug was identified that, although having excellent bioavailability, exhibited unacceptable pharmacokinetics. Based on in silico modelling and a site of absorption study it was confirmed that creating an extended release formulation could provide the desired pharmacokinetic profile. The optimised formulation showed good antiviral activity when dosed employing a once or twice a day regimen.
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb, Reeds Lane, Moreton, Merseyside CH46 1QW, UK. Electronic address: peter.timmins@bms.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Timmins
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb, Reeds Lane, Moreton, Merseyside CH46 1QW, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Brown
authors.affiliation: Global Clinical Research, Bristol-Myers Squibb, Route 206 and Province Line Road, Princeton, NJ 08540, USA.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.affiliation: Global Clinical Research, Bristol-Myers Squibb, Route 206 and Province Line Road, Princeton, NJ 08540, USA.
authors.forename: George J
authors.initials: GJ
authors.lastname: Hanna
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Hopewell, NJ 08534, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Discovery Chemistry, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Kadow
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D003198:Computer Simulation; D016503:Drug Delivery Systems; D015195:Drug Design; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000302:isolation & purification; D006801:Humans; D011355:Prodrugs; D012995:Solubility
chemical_list: D019380:Anti-HIV Agents; D011355:Prodrugs