Pharmacokinetic (PK) assessment of small molecule compounds is essential from the early stage chemical lead identification. PK testing remains critical during the lead optimization stage to demonstrate the Structure-Activity Relationships (SAR), as also the Structure-Property Relationships (SPR).

PK analysis of new chemical entities typically involves absorption, distribution, metabolism, and elimination/excretion (ADME) studies. PK parameters determine which small-molecule chemical entities will enter the stage of Investigational New Drug (IND) application.

PK Parameters To Determine The Viability of Drug Compounds

PK parameters typically consist of:

• Bioavailability: The MSD Manual defines bioavailability as the rate at which drug moiety enters systemic circulation to access the action site. Also, the extent of drug moiety reaching the site of action,
• Clearance: A textbook of applied biopharmaceutics defines drug clearance as the volume of fluid freed of the drug @ millilitres per minute (mL/min) or litres per hour (L/h).
• Volume Distribution: Vd refers to the propensity of a drug to remain concentrated in the plasma or distribute itself to other tissues. Vd is the proportionality of the total drug in the body in relation to the presence of the drug in the plasma at a given point of time.
• Plasma Elimination Half-Life: This refers to the time necessary for the drug concentration in the plasma to become 50% of the original dose.

The University of Lausanne’s (UNIL) Department of Biology and Medicine explains that the half-life of a drug depends on its volume of distribution and clearance. The volume of the drug present in the body does not affect its elimination half-life.

In recent years, we have witnessed the introduction of higher throughput methods of PK analysis. These PK testing techniques with heightened sensitivity have considerably increased the efficiency level of PK data generation.

Compartmental vs Noncompartmental PK Analysis

A practical guidebook for medicinal chemists explains that at the early stage of drug discovery, noncompartmental PK analysis methods are usually sufficient for assessing most of the PK parameters. Software packages are commercially available for such noncompartmental analysis.

However, it is also possible to do such analyses using a simple calculator or Microsoft Excel.

Compartmental analysis of PK testing results become necessary to understand the mechanistic aspects of drug disposition. Such investigations typically relate to the number of distinct body compartments, the movement of the drug in each compartment, metabolism rates, sequential metabolism, and multiple pathways for excretion.

Experts advise the use of software packages tailored for pharmacokinetic data analysis in the case of compartmental analysis. This is typically necessary at a later stage of drug compound development.

A compartmental analysis is robust enough to facilitate future predictions, simulations, and treatment of PK-PD. A non-compartmental analysis is not useful for these functions.

A Two-Tier Approach To PK Data Analysis For Lead Optimization

Experts recommend a two-tier approach for efficient assessment of PK parameters at both in-vitro and in-vivo levels. The flowchart below explains the process:

This two-tier approach during the in-vitro stage helps to optimize the ADME properties of the drug compound before actual animal dosing. The two-tier approach during the in-vivo stage facilitates the rapid assessment of compound exposure (RACE).

This two-tier approach got developed in the National Institute of Health’s (NIH) Molecular Libraries Program (MLP). It serves as a good practice model for PK data assessment in small molecule drug development.