RT Journal Article
SR Electronic
T1 Plasma protein binding as an optimisable parameter for acidic drugs
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.119.087163
DO 10.1124/dmd.119.087163
A1 Philip Gardiner
A1 Rhona J Cox
A1 Ken Grime
YR 2019
UL http://dmd.aspetjournals.org/content/early/2019/05/21/dmd.119.087163.abstract
AB The low volume of distribution associated with acidic molecules means that clearance 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 optimisation 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 whilst 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 optimisation of acidic CXCR2 antagonists for the oral drug treatment of inflammatory diseases, resulting in discovery and clinical testing of AZD5069 and AZD4721, orally bioavailable acidic molecules with PPB of <1%, human hepatocyte intrinsic clearance values < 5 µl/min/106 cells and predicted human Vss < 0.3 L/kg, resulting in effective half-lives in man of 4 and 17 h respectively.SIGNIFICANCE STATEMENT Provided that pharmacological potency is high enough, modulation of plasma protein binding can form part of a viable strategy in drug discovery to optimise effective half-life of drug candidates in humans.