Plasma Protein Binding as an Optimizable Parameter for Acidic Drugs.
Drug Metab Dispos
; 47(8): 865-873, 2019 08.
Article
em En
| MEDLINE
| ID: mdl-31113795
ABSTRACT
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 (V ss) <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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Sanguíneas
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Receptores de Interleucina-8B
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Inflamação
/
Anti-Inflamatórios
Tipo de estudo:
Clinical_trials
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article