PK-PD Assay Development: Determine Drug Exposure, Target Modulation, And Physiological Effects

Pharmacokinetics-pharmacodynamics (PK-PD) assays are an integral facet of the drug development domain. Today study data from adequate PK assay complemented with PD analysis are used in PK-PD modelling to quantify drug exposure, target modulation, and physiological effects of the drug molecule. The resultant PK-PD assays form a crucial link between target modulations and safety and efficacy outcomes. They further pave the way for accurate dosing schedules.

Drug modulation, drug exposure, and physiological effects

A pharmacokinetic study is responsible for studying the drug time course in the body, whereas a pharmacodynamic study evaluates the pharmacological effects in the body. Hence, a quantitative PK-PD approach is a prerequisite for successful drug development and its translation to an established relationship between a drug and its observed effects in the body. A PK-PD approach aids in characterizing the exposure-response relationship that eventually increases the success probability of a candidate drug molecule. However, this success is substantially dependent on the attributes of the assay protocol used in PK-PD modelling. Similar to PK assays, the development of efficient PD assays will facilitate quantitative drug effect evaluation that comes before the desired clinical outcomes and can be exploited as a potential surrogate endpoint. Such upstream evaluation will further help in the early detection of physiological effects, often before the primary clinical outcomes, and justify the dosage regimen in extensive clinical trials. By default, the first step in a PK-PD assay is the drug-target interaction and depends on the type of drug molecule. For example, in the case of protein drugs, a complete understanding of the biomolecular interaction is necessary when binding modulates total drug clearance, reduces free drug concentration, and mediates the target's concentration and kinetics. Once the target is modulated, it results in a cascade of downstream events that can produce concentration-dependent responses to escalating drug exposure. The precise estimation of some prime model parameters, such as molecular species concentration and proportionality constants, largely dictates the successful modelling of PK assays and target modulation. Although a robust and effective PK-PD model will quantify all molecular species, it is not a prerequisite for a predictive PK-PD model. A PK-PD assay can be based upon the total or free drug levels and the target levels in a single molecular state, primarily when supported through in vitro data. The analyte of choice is also based on several factors, such as practicality, modelling utility, and clinical and bioanalytical feasibility. Thus, a PK-PD assay is predominantly dependent on the type of data provided during assay protocols.

Conclusion

Over the years, research has shown how a better understanding of drug molecules can alter a drug candidate's PK analysis. Target-mediated disposition study models responsible for the target engagement perfectly sums up PK bioanalysis and PK testing complexity. The availability of robust PK-PD study data will facilitate quality and efficient assessment of PK analysis, target modulation, drug effects, and target expression through mechanistic PK-PD models. Furthermore, the data obtained will allow the formation of quantitative system models incorporating disease pathophysiology, drug pharmacology, and biological pathways into predictive drug models.