The Role of PK Labs in Predicting Drug Absorption and Metabolism
What is PK Analysis?
Pharmacokinetics (PK) is the discipline within the domains of pharmacology that deals with what happens to a chemical substance that enters the body over time. This discipline of study is extremely crucial in the context of a pharmaceutical agent or drug. PK analysis is essentially a part of the preclinical trials that help determine how the drug would behave in vivo. When the drug discovery processes reach the end of the lead compound optimization and identification of a few potential drug candidates, PK analyses are performed for them. On the other hand, PK analysis in clinical trials helps assess the pharmacokinetics of a drug in an individual patient. PK analysis in clinical trials determines how an administered drug is absorbed, distributed, metabolized, and excreted in the body. Positive results of PK analysis are crucial in drug development. Results from PK analysis during preclinical trials help in designing clinical trials. However, both these results help to inform drug development of the safety and efficacy of the drug.
In addition to PK analysis in preclinical and clinical trials, the PK of a drug molecule is also assessed for scale-up batches to identify changes that might have occurred during the synthetic chemistry processes in scale-up or due to variation in its purity.
How is PK Analysis Done?
In PK clinical trials, biological samples are collected from the individuals participating, and the drug concentration is calculated as a function of time. From the plot of drug concentration versus time, different PK parameters are estimated, providing crucial information about the absorption, distribution, metabolism, and excretion (ADME) properties of the drug and its metabolites. Some of the key PK parameters are AUC (area under the curve represents the total drug exposure as a function of time), Cmax (the maximum observed concentration of drug measured after dosing), F% (represents bioavailability of the drug, i.e., the fraction of dose absorbed), and t1/2 (disposition half-life).
PK Labs
Pharmacokinetics labs offer services that facilitate drug development in pharmaceutical companies and research in biotechnological industrial and research institutes. They develop and validate analytical methods for toxicokinetic, pharmacokinetic-anti-drug antibody (PK ADA), and Pharmacokinetic — Pharmacodynamic (PK PD) analyses for pharma and biotech companies and research institutes. In addition, some offer support in data collection and analysis and regulatory submissions from drug discovery to clinical trials, thus helping researchers focus on their key research goals.
PK labs use diverse analytical instruments for the PK analysis of drugs. The choice of instrumentation is largely determined by the type of analyte, matrix, and required concentration range. The chosen method, however, should be accurate, precise, reproducible, and robust; they should be validated before their application. For large molecules and biosimilars, ligand binding assays, such as ELISA, MSD, RIA, etc., are used. On the contrary, most small drug molecules are analyzed using liquid chromatography (HPLC and UPLC) followed by mass spectrometry-based detection (MS and MS/MS). Mass spectrometric methods help in the rapid quantification and characterization of analytes. In addition to mass spectrometry, other detectors, such as fluorescence, UV/Vis, phosphorescence, etc., may be used.
Thus, bioanalytical services offered by pharmacokinetics labs include development and LCMS method validation based on FDA guidelines, along with other biological assay methods; in vitro ADME determination which includes microsomal stability, plasma stability, cytochrome P450 inhibition and reaction phenotyping, solubility, plasma protein binding, blood to plasma ratio, Caco-2, etc.; and, PK testing in animals such as rodents which include the determination of drug bioavailability.
PK analysis during preclinical research helps to flag potential safety risks associated with a drug, e.g., toxicity or drug-drug interaction. It also helps to determine the optimal dosing regimen of a drug. This includes the route of administration, dosage, and frequency of drug administration. This helps to assess the optimal drug dosage for the desired therapeutic outcome. PK PD analysis helps to correlate the concentration of the drug or its metabolite at a particular site in the body to its physiological and/or behavioral effects. PK ADA analysis, on the other hand, helps assess the immunogenicity of new biosimilars. PK studies are first conducted in animal models, followed by PK clinical trials, since the results from the former help to design the clinical trial and interpret PK clinical trial data.
How Does PK Analysis Help to Predict Drug Absorption and Metabolism?
Drug concentration and duration for which the drug stays in the target site within the body are linked to its effect. Variation in drug concentration as a function of time depends on the relative rates of ADME processes in the body. PK analysis helps to estimate various biological parameters inherent in the ADME processes that control drug activity and thus helps optimize drug dosage. Most PK studies use blood and plasma samples since it is extremely challenging to determine drug concentrations in tissues. In most cases, the concentration of drugs in plasma correlates well with their activity.
PK analysis plays a crucial role in drug discovery and development. It is a key tool for designing and optimizing therapeutic dosage regimens, and PK labs offer services to dedicated support towards this end.
