Designing safer oral drugs.

Area of Science:

• Pharmacology
• Drug Discovery
• Toxicology

Background:

• Designing safe and effective oral drugs is challenging, especially with limited early-stage safety data.
• Current methods rely on physicochemical properties and log P for guidance, but these have limitations.
• Understanding the relationship between drug properties and human toxicity is crucial for drug development.

Purpose of the Study:

• To propose an alternative heuristic criterion for designing efficacious oral drugs with reduced toxicity.
• To establish a threshold for the amount of compound in the body at steady state in humans.
• To provide a method for assessing a compound's estimated in vivo plasma levels against a therapeutic window.

Main Methods:

• A novel criterion based on the amount of compound in the body at steady state was developed.
• This criterion was established using minimum toxic blood-plasma concentration data from 242 oral drugs.
• The proposed threshold for humans is 0.5 mg/kg.

Main Results:

• A steady-state amount of 0.5 mg/kg is proposed as a human threshold for oral drug design.
• This criterion can be used to estimate a therapeutic window for new drug candidates.
• The study discusses the relationship between this criterion, oral dose sizes, charge types, and in vivo plasma clearances.

Conclusions:

• The proposed steady-state amount criterion offers a new heuristic for designing safer and more effective oral drugs.
• This approach can aid in early-stage drug design by predicting potential toxicity liabilities.
• Further assessment of estimated in vivo plasma levels against this threshold can guide dose selection and optimization.