Pharmacokinetics (PK) is the study of time course of drug’s or compound’s concentration in the body (what the body does to the drug or compound). The concentration profile of a compound or drug in the body is the result of the processes of Absorption (A), Distribution (D), Metabolism (M) and Elimination (E) or ADME. Most importantly the concentration of a compound in the body is linked to its efficacy or toxicity. Hence, characterizing the PK of a compound early on in discovery programs helps in evaluation of its drug-like properties.
Fundamental PK parameters such as Volume of Distribution at steady state (Vss), Systemic Clearance, elimination half-life, the Area Under the Concentration Time curve in blood (AUC), Peak concentration in blood (Cmax), time to peak concentration in blood (Tmax), and Oral Bioavailability help in understanding the compound’s ability to show efficacy or toxicity in animals and human beings. Determination of PK parameters in preclinical studies help in optimizing molecules for efficacy and safety, progression to crucial pharmacology and toxicology studies, in prediction of human PK using Allometric scaling and Physiologically Based Pharmacokinetic (PBPK) and in Pharmacokinetic/Pharmacodynamic (PK/PD) modelling.
The relationships between the time course of drug or compound concentration (Pharmacokinetics, PK) and the onset, intensity and duration of pharmacological effect (Pharmacodynamics, PD) form the basis for evaluation of the drug’s efficacy and potency (referred to as Quantitative Pharmacology) in preclinical animal models of disease and in human patients.
Determining PK/PD relationships for compounds early on in discovery programs help in a) progression of the optimum compound for advanced testing; b) prediction of efficacy and potency based on in vitro and PK data; c) prediction of efficacy in humans by extrapolation of preclinical PK/PD models; and most importantly in setting dose, regimen and duration in pre-clinical pharmacology studies and in humans.
The in vivo Pharmacokinetics (PK) and Pharmacodynamics (PD) of a compound or drug can be represented as mathematical models. Developing PK, PD or PK/PD models help in simulations of what-if scenarios such as prediction of quantitative pharmacological effect when a compound is given as single, two or three doses in a day, concentration-time profiles for different doses and regimens, time needed for complete efficacy.
Such simulations help in designing optimal experiments, selection of time points for collection of data, prediction of effect in long duration studies thus avoiding time consuming studies, and prediction of PK and PD profiles in human populations. Modelling and Simulation (M&S) is a powerful tool in drug discovery and development and is being increasingly sought by the regulatory authorities for decision making.