A dose goes in, and then a sequence of events follows that nobody can watch directly: the compound is absorbed, carried around the body, chemically altered, and finally removed. Which tissues it reaches, how long it stays there, and in what form it leaves are the questions Pharmacokinetics (PK) sets out to answer.
Pharmacokinetics (PK) is the study of the movement and change of substances in living organisms. These substances can be any chemicals that come from outside the body, such as drugs, pesticides, food additives, and cosmetics. PK analyzes how the body affects the drugs in terms of absorption, distribution, metabolism, and excretion (ADME). Conversely, Pharmacodynamics (PD) studies how the drugs affect the body. Together, PK and PD determine the dose, benefit, and side effects of drugs, and are often studied together as PKPD. A dose only means something when both halves are known.
Why PK Matters In Development
PK is important for drug discovery and development, as it helps to optimize the drug delivery, efficacy, and safety. PK also helps to adjust the drug dosage and regimen for different patients, based on their demographic, physiological, and pathological characteristics, as well as their co-treatments. A compound that never reaches its target at a tolerable exposure will fail however potent it is in vitro. PK can also be applied to ecological toxicology, to study the impact of harmful chemicals on the biosphere and the environment.
Models And What They Assume
PK uses mathematical models to describe and predict the concentration-time curves of drugs in the body. These models can be based on compartments, which are hypothetical spaces that represent different tissues or fluids in the body, or on non-compartmental methods, which rely on estimating the total exposure of the drug by calculating the area under the curve (AUC). Non-compartmental analysis is usually the first readout, because it assumes less; PK Statistics: Non-compartmental Analysis (NCA) Parameters And Preclinical Applications sets out what those parameters describe.
PK models can be simple, such as the one-compartment model, which assumes that the drug is evenly distributed and eliminated from the body, or complex, such as the physiologically based pharmacokinetic (PBPK) model, which incorporates physiological information to simulate the drug behavior in the body. PBPK Vs. Compartmental Models: Why PBPK Matters covers that trade-off in practice.
Bioavailability, Clearance, And Half-Life
One of the key concepts in PK is bioavailability, which is the fraction of the drug dose that reaches the systemic circulation. Bioavailability is influenced by many factors, such as the drug formulation, chemical form, route of administration, stability, and metabolism. Bioavailability is used to compare the drug exposure between different delivery methods, such as oral, intravenous, or transdermal. For example, intravenous injection provides the highest bioavailability, as the drug directly enters the bloodstream, while oral administration may reduce the bioavailability due to the first-pass effect, which is the metabolism of the drug by the liver before it reaches the circulation.
Another important concept in PK is clearance, which is the rate at which the drug is removed from the body. Clearance can be affected by the blood flow, the organ function, and the drug interactions. Clearance is used to calculate the elimination half-life, which is the time it takes for the drug concentration to decrease by half. The elimination half-life determines how often the drug needs to be administered to maintain a steady state, which is the condition where the drug intake and elimination are balanced. Dosing before that balance is reached accumulates the drug, and dosing well after it wastes exposure.
PK turns these questions into numbers, and it is why ADME work sits near the front of most development programs. By applying PK principles and methods, we can improve the drug design, delivery, and dosing, and in the end enhance the health and well-being of humans and other living beings. Where exposure and effect are analyzed side by side, as in Integration Of Pharmacokinetics And Pharmacodynamics in Drug Development, the output is a dose that a first-in-human study can start from.
