Effective pharmacokinetics and pharmacodynamics (PK/PD) studies require input from different complementary disciplines within a bioanalytical lab. PK/PD studies will generate desirable results when optimally designed and conducted with inputs from all pertinent experts. Such a report will reflect and integrate relevant data and capture assumptions made during the analysis, and suggest subsequent evaluation for more robust and reliable research.
The primary aim of early drug development studies is to identify promising compounds and potentially effective and safe drug doses. Integrating effective PK/PD data in the early drug discovery phase can help identify potentially safe and effective drug compounds and lower the rate of downstream attrition in subsequent clinical trials. However, analyzing complex PK/PD data will require approaches for interpreting assay results. Hence the current article focuses on strategies for data visualization and interpretation.
Data visualization and interpretation strategies for analyzing complex PK/PD data
Analyzing PK/PD data from complex studies such as ADA detection assay can be difficult. ADA assay development is crucial for developing and determining antibodies and neutralizing antibody assay (nAb). ADA nAb assays are conducted to detect immune responses against biological products. Biologics can induce an immune response; therefore, ADA and nAb assays are vital for the successful development of biologics products. Immunogenicity testing employs the approach which begins with screening assays followed by confirming ADA formation. Finally, the nAb assay evaluates the neutralizing activity of an antibody to verify whether it affects the therapeutic activity of a biological product.
The initial approach to assessing PK/PD data is correlating concentration versus time curve for PK analysis and effect versus time profiles for PD data. However, researchers may plot concentration versus effect and remove the time variable to correlate between PK and PD data sets. Moreover, this relationship can either be direct or indirect.
Although plotting concentration versus affect data is ideal for assessing PK/PD characteristics, the ultimate choice of model will be decided by the available data points. Generally, PK/PD analysis falls into temporal delayed and instantaneous effects.
Temporal delay effects of pharmacodynamic data can be due to several reasons, including indirect action, active metabolites, distributional delay receptor, activation kinetics, and modification in baseline over time. However, researchers may employ different models, such as PK/PD receptor-based and indirect response models, to demonstrate a disconnect between pharmacological effect and plasma concentrations.
On the other hand, instantaneous effects are directly mediated concentration effects when a drug compound reaches instant equilibrium with the biophase. In such cases, researchers can characterize PD relationships using models ranging from simple linear systems to complex sigmoidal Emax models. Most models have a baseline response, but other models, such as long simple linear and exponential models, operate under the assumption that the drug effect is not finite. Moreover, in scenarios where the PD response has reached a maximum effect, Emax models are an ideal choice of system to describe the observed data points.
In conclusion, a thorough analysis of PK/PD data is crucial in understanding the mechanism of drug action, comparison between different potential drug compounds, and selecting ideal drug compounds for subsequent development.