Pharmacokinetic (PK) analysis is necessary at different stages of drug development. Simply put, a PK study is necessary to determine how the human body affects the drug over time. PK assays are needed from the first phase of drug discovery to the final stage of clinical trial.
Significant development has happened in pharmacokinetic study techniques over time. A number of national and international agencies have also been collaborating to standardize bioanalytical method development and validation techniques across the globe. These efforts also have implications for PK testing methods.
This article presents an overview of PK analytical testing specifically during the drug discovery phase. It includes information on the latest developments through an extensive review of relevant literature.
Evolution in the Role of PK Assays
PK assay focus mostly on the safety aspect of drugs. PK studies contributed more towards indicating the failure of potential new drugs till the early 1980s. Since the mid-1980s, however, PK analyses have undergone a radical realignment to facilitate the selection of drug candidates with optimal probability of success.
The basics of what we know today as PK theory and analysis got established in the 1960s. However, PK assays did not become integral to the drug discovery and development process until the 1980s. Developments in four interrelated areas made PK optimization an achievable goal in the drug discovery process.
The first of these developments happened in the field of bioanalytics. The development of thermospray interfacing enabled the combining of high-performance liquid chromatography (HPLC) with triple quadrupole mass spectrometry (LC-QqQ-MS/MS).
The second development was in the field of mathematics in the form of clearance concepts in pharmacokinetics. These allowed deriving the area-under-the-curve (AUC) from the dosage. They also facilitated the process of calculating the elimination rate from drug concentrations.
The third development happened in the domain of experiments. The development of in vitro metabolizing systems facilitated predictions about clearance from animal liver preparations. That extended to forecasting clearance from human liver preparations also.
Chronologically speaking, conceptual clarity about the tremendous potential of drug metabolism combined with pharmacokinetics (DMPK) in drug discovery occurred last. This clarity came with the realization that chemical and physicochemical properties drive DMPK traits.
These four developments have led to tremendous progress in DMPK science. It has now become integral to the drug discovery process. The practical aspects necessary to implement cost-effective and efficient DMPK analyses are very much in place today.
How PK Assays Facilitate Drug Discovery
The pharmaceutical industry currently functions amidst a fair amount of pressure. There are budgetary constraints. Regulatory compliance needs are on the rise. Commercial pressure combines with societal scrutiny as well. Research and development (R&D) initiatives in the industry naturally focus on reducing attrition.
The progress DMPK science has achieved in the detailed and in-depth understanding of the absorption, distribution, metabolism, and elimination/excretion (ADME) processes plays a key role in arresting attrition. Enhanced understanding of drug-drug interactions also contributes.
Today, there are guidelines and benchmarks available to optimize ADME studies to fully understand the PK properties of new chemical entities. That is crucial at the first stage of lead selection. Also at the later stage of lead optimization to explain the structure-activity relationship (SAR) and structure-property relationship (SPR).
