RT Journal Article
SR Electronic
T1 Plasma Protein Binding as an Optimizable Parameter for Acidic Drugs
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 865
OP 873
DO 10.1124/dmd.119.087163
VO 47
IS 8
A1 Philip Gardiner
A1 Rhona J. Cox
A1 Ken Grime
YR 2019
UL http://dmd.aspetjournals.org/content/47/8/865.abstract
AB 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.