TY - JOUR T1 - Plasma Protein Binding as an Optimizable Parameter for Acidic Drugs JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 865 LP - 873 DO - 10.1124/dmd.119.087163 VL - 47 IS - 8 AU - Philip Gardiner AU - Rhona J. Cox AU - Ken Grime Y1 - 2019/08/01 UR - http://dmd.aspetjournals.org/content/47/8/865.abstract N2 - The low volume of distribution associated with acidic molecules means that clearance (CL) must also be very low to achieve an effective half-life commensurate with once or twice daily dosing. Plasma protein binding (PPB) should not usually be considered a parameter for optimization, but in the particular case of acidic molecules, raising the PPB above a certain level can result in distribution volume becoming a constant low value equal to the distribution volume of albumin while acting to reduce CL through restricting hepatic and renal access of unbound drug. Thus effective half-life can be increased. Here we detail the approaches and lessons learned at AstraZeneca during the optimization of acidic CXC chemokine receptor 2 (CXCR2) antagonists for the oral drug treatment of inflammatory diseases, resulting in discovery and clinical testing of N-[2-[(2,3-difluorophenyl)methylsulfanyl]-6-[(2R,3S)-3,4-dihydroxybutan-2-yl]oxypyrimidin-4-yl]azetidine-1-sulfonamide (AZD5069) and AZD4721, orally bioavailable acidic molecules with PPB of <1%, human hepatocyte intrinsic clearance values <5 µl/min per 106 cells and predicted human volume of distribution at steady state (Vss) <0.3 l/kg, resulting in effective half-lives in humans of 4 and 17 hours, respectively.Significance Statement Provided that the pharmacologic potency is high enough, modulation of plasma protein binding can form part of a viable strategy in drug discovery to optimize the effective half-life of drug candidates in humans. ER -