Optimizing DMPK Properties: Experiences from a Big Pharma DMPK Department.

Area of Science:

• Pharmacology and Drug Discovery
• Medicinal Chemistry
• Biotechnology

Background:

• Drug disposition relies on drug properties, body interactions, and biological barriers.
• Achieving therapeutic effects requires drugs to reach target sites at adequate concentrations.
• This review focuses on the role of drug metabolism and pharmacokinetics (DMPK) and physicochemical properties in compound optimization at AstraZeneca.

Purpose of the Study:

• To present key assays for evaluating DMPK properties of new chemical entities.
• To guide the interpretation of assay outcomes for effective compound optimization.
• To describe an integrated approach for predicting drug fate in humans early in discovery.

Main Methods:

• Utilized assays for solubility, LogD, permeability, and metabolic stability in early drug discovery.
• Implemented high-throughput methods for efficient bioanalysis and sample handling.
• Integrated in vitro data for early "dose to man" predictions, refined with in vivo pharmacokinetic (PK) and pharmacodynamic (PD) data.

Main Results:

• Developed a streamlined workflow for DMPK activities from lead identification to candidate selection.
• Achieved cost-effective and efficient optimization of chemical series.
• Facilitated informed decision-making throughout the drug discovery project lifecycle.

Conclusions:

• A robust DMPK workflow enhances efficiency and cost-effectiveness in drug development.
• Early and integrated assessment of DMPK properties is crucial for successful compound optimization.
• Informed decision-making, supported by comprehensive data, drives successful drug candidate selection.