Safety concerns emerging from animal toxicity testing constitute one of the significant factors of Drug candidate elimination. Safety issues sometimes arise during the clinical stage also.

Pharmacokinetic (PK) testing is a critical method to address safety issues at the early stages of drug development. Adequate PK profiling of a potential drug candidate allows quantification of the risks involved in systemic drug exposure.

PK Studies typically focus on the concentration vs time aspect of new drug candidates. For a comprehensive safety and efficacy profiling of a new drug compound, we also need pharmacodynamics (PD) studies focused on effect vs time profiling.

The Role of PK Profiling In The Drug Development Process

PK analysis and the interpretation of the data obtained in the early phase of drug discovery determines what kind of additional PK data will be necessary at the next study stage. This continues throughout the drug development process.

Efficient and effective pharmacokinetic (PK) testing, along with pharmacodynamics (PD) studies require a multidisciplinary approach.

DMPK (drug metabolism and pharmacokinetics) laboratories usually carry out the PK analysis part of PK/PD studies. The focus of PK studies is typically on measuring the drug

concentration levels and other PK properties.

Pharmacological laboratories conduct the pharmacodynamics part of PK/PD studies. The focus is on animal dosing and response profiling.

With different kinds of laboratories involved, the animal used for PK studies and PD studies can vary. This needs careful integration of PK/PD study results. Inputs from mathematical modelling experts are also crucial for formulating an efficient strategy of clinical development.

There Is Room To Improve PK Analysis

Pharmaceuticals is the only industry that continues to have a failure rate of over 90%. There have been remarkable advancements in PK testing methods. But the success rate of drug compounds entering phase 1 of clinical trials continues to be marginally below 10% since the 2000s.

Clearly, there is room for improvement in the preclinical PK analysis and PD study processes. Safety and/or efficacy issues constitute the reason behind 75-80% of the failures.

Proposed Improvement Parameters

Experts propose the following critical benchmarks for efficient PK/PD studies that can reduce failure rates:

• Establish a collaborative team of a biologist, a chemist, a disease area pharmacologist, and a DMPK scientist.
• This multidisciplinary team needs to establish a working hypothesis for testing in subsequent studies.
• The team of experts needs to keep refining the hypothesis based on emerging PK/PD data
• Conduct an acute pilot PK/PD model to explore the exposure-response relationship.
• Establish the iterative PK/PD modelling protocol based on the initial findings
• Establish clearly defined objectives for this iterative process
• Use the same animals for PK and PD studies
• Focus on obtaining well-defined AUC, Cmax, and Tmax profiles along with appropriate PD biomarkers
• Capture details of concentration and effect correlation

A Point To Remember

We can now apply efficient and effective PK/PD studies during the preclinical stages of biologics development also. Successful PK/PD profiling at the preclinical stage minimizes the chances of failure at the first phase of a clinical trial.