Effective pharmacokinetics and pharmacodynamics (PK/PD) assays during drug development require input from different scientific disciplines. Most often, PD assays are conducted by the pharmacology department, whereas DMPK laboratories perform pharmacokinetic assays. In many scenarios, pharmacokinetic evaluations are not even conducted in the same animal used for pharmacodynamic assessments. Hence pharmacokinetic and pharmacodynamic data points may come from independent studies performed in different laboratories and even at different periods.
Ideally, PK/PD assays should be designed and conducted by both pharmacology and DMPK experts. Such a comprehensive analysis will integrate all relevant data points and address the required hypothesis or questions outlined in a particular study. Besides, the study will consider all assumptions and suggest modifications to enable an effective PK/PD analysis. The current article discusses PK/PD assays.
PK/PD assay: Changing the drug development landscape
PK/PD assays can effectively provide pharmacological data on a drug compound. Generally, study designs are based on the causal relationship between drug exposure and its therapeutic activity. However, such study designs are complex. Hence a powerful PK/PD model will generate relevant information. Robust PK/PD models during early drug discovery and development initiatives can shorten the drug development timeline, minimize animal use, predict effective dose ranges and estimate the therapeutic index.
The initial approach to PK/PD modeling should:
- Established DMPK and pharmacological relationship
- Conduct initial PK/PD analysis
- Define the hypothesis
- Refine and implement the strategy
A typical workflow of a PK/PD study design begins with in vitro and in vivo studies that can help design the study model. Secondly, the acute preliminary PK/PD model examines the exposure and response relationship. This model is generally simple and short, with the primary objective to assess efficacy. The entire screening and setup process of a PK/PD assay is usually an iterative approach requiring continuous refinement as a drug development project moves forward.
Generally, PK/PD analysis requires samples from the same animals. However, collecting samples from the same animals for pharmacokinetic and pharmacodynamic readouts can often be challenging. Here researchers can employ a satellite group of study animals. In such cases, it is vital to match all features of the study design, such as species, strain, gender, disease state, dosage, and operator. Moreover, when a satellite group is unavailable , investigators can opt for a bridging experiment involving alternative strains to instill confidence in the study design.
Post design and execution of PK/PD assays, investigators acquire data sets from that specific study. A thorough analysis of these data sets is critical to understanding the mechanism of drug action and comparing different compounds to select an optimal candidate for further stages of drug development. Some crucial aspects of PK/PD data analysis and interpretation include:
- Correlating drug concentration and effects
- Selecting an appropriate PK/PD assay
- Determining the relationship between in vitro potential and in vivo drug levels
- Evaluating binary response and multiple biomarker data
- Confirming variability between PK and PD data sets
- Translating drug compounds from pre-clinical PK/PD studies to subsequent clinical testing
PK/PD assays are vital for accelerating drug development studies and translating a drug compound from pre-clinical drug development to subsequent clinical trials.