Variability in drug response as a factor in drug design

Area of Science:

• Pharmacology
• Drug Development
• Medicinal Chemistry

Background:

• Drug response variability is a significant challenge in clinical practice.
• This variability can originate from pharmacokinetic (PK) or pharmacodynamic (PD) factors.
• Understanding these sources is crucial for effective drug design.

Purpose of the Study:

• To analyze the sources of variability in drug response.
• To identify targets for drug design to minimize inter-individual differences.
• To explore strategies for improving drug efficacy and safety through PK/PD optimization.

Main Methods:

• Review of the classical pharmacokinetic/pharmacodynamic (PK/PD) model.
• Analysis of factors contributing to PK variability, including absorption, clearance, and metabolism.
• Consideration of PD variability due to drug target polymorphisms.
• Evaluation of patient-related factors like compliance and dosing regimens.

Main Results:

• Pharmacokinetic variability arises from absorption, clearance, and metabolism (e.g., polymorphic CYP450 enzymes like CYP2D6, CYP2C19).
• Pharmacodynamic variability can be influenced by drug target polymorphisms (e.g., beta(2)-adrenoceptor).
• Patient compliance and dosing convenience (e.g., once-daily regimens, minimizing food/drug interactions) are critical factors.

Conclusions:

• Drug design should address PK variability by optimizing physicochemical properties and avoiding polymorphic metabolism.
• Achieving target selectivity is essential to manage PD variability and minimize side effects.
• Enhancing patient compliance through user-friendly dosing regimens is a key strategy for reducing drug response variability.