The term “Pharmacokinetics” is derived from “pharmakon” and “kinetikos” in ancient Greek, meaning “drug” and “position in motion,” respectively. It is one of the principal assessments in the drug development process that describes what the body does to an administered drug substance and is essential data for defining safe and effective levels of drug to be administered.
Currently, in drug development, there is a large variety of drug moieties with variable structures and pharmacological actions. Examples include small molecules, recombinant human proteins, fusion proteins, synthetic peptides, oligonucleotides, monoclonal antibodies, bi- and tri-specific antibodies, antibody drug conjugates, and even cell and gene therapies. A fundamental assessment for these compounds is to understand their pharmacokinetics once administered to the subject.
It is essential to measure and understand the pharmacokinetics of the unbound fraction of the medicine since it is the fraction that interacts with the target receptor and results in the desired or undesired effects (i.e. pharmacodynamics). Some non-peripheral targets may be problematic (i.e. CNS). To describe the drug effect, it is important to understand the mechanisms involved in the intake and efflux of efficient and plasma-based compartments.
Even though oral administration is the most common route for small molecule therapeutics, pharmacokinetic oral bioavailability still poses special problems because of the complexity of the absorption process. Before reaching the systemic circulation, a medication must be absorbed from the GI tract wall into the portal vein and into the liver where it faces two pharmacokinetically challenging processes; absorption and metabolism; the name ‘first pass effect’ reflects those challenges. The total part of the medicine that enters the central compartment (i.e. the plasma) through the oral route (“F”) is a product of the absorbed fraction (fa) and the fraction that escapes through the liver metabolism (fh). The fraction represents the systemic oral availability, which is one of the most commonly studied pharmacokinetic processes.
The process of pharmacokinetics (PK) describes the changes in the amount of a medicine in the body over time and is essential for understanding the pharmacodynamic (PD) process of a medicine (i.e. the resultant drug effects or adverse effects). The assessment of PK and PD is crucial for ensuring drug safety and efficacy as investigated in preclinical as well as Phase I, II and III clinical studies. The pharmacokinetics can be expressed quantitatively by calculation of PK parameters such as an elimination constant (Ke), half-life (t1/2), distribution volume (Vd) and clearance (CL). The pharmacokinetic analysis is most commonly performed using two approaches; compartmental and noncompartmental. Noncompartmental analysis is currently the most popular and is similar to kinetic analysis used in other scientific disciplines such as chemical kinetics and the theory of chromatography, both are analyzed using the principles of statistical moments. The non-compartmental analysis explores the exposure to a drug through an estimate of its area of the concentration-time graph under the curve (AUC) and moment curve (AUMC), which is more versatile, since very little is based on the compartmental assumptions or in vivo drug processes. The compartment model describes the concentration-time profiles where the body is considered as one compartment or series of compartments as dictated by the shape of the plasma-concentration curve. To clarify the analysis of pharmacokinetics, a series of functional models have been developed which are based on the organism being considered as a series of similar compartments.
Key PK parameters (such as bioavailability, plasma elimination half-life, clearance, and volume of distribution) can be generated from PK profiles following oral and intravenous dosing. With the introduction of more sensitive, higher-data analysis methods, the efficiency of PK data generation has improved in recent years. Furthermore, cannulated animal techniques yield more accurate and less variable PK parameters and cassette dosing accelerates the screening of drug molecules. In cassette dosing studies, up to 10 structurally similar drug molecules are dosed simultaneously to the same animal, yielding 10 times the amount of PK information obtained from conventional PK studies. Additional in vivo PK data that can provide important insights can be acquired through the interruption of the common bile duct or gallbladder in bile excretion studies.
Five PK Parameters
For therapeutics, five pharmacokinetic parameters are important:
Bioavailability – Therapeutic bioavailability partially depends on the drug’s formulation. When it first passes through the liver, a substance that is highly metabolized shows a significant first-pass effect which reduces the efficient oral consumption of the drug. A reduction in that initial effect may cause a clinically relevant increase of effective oral drug absorption e.g., due to reduced hepatic blood flow in cardiac failure.
Volume of distribution and distribution phases – After a loading dose, the volume of the drug distribution determines the level of the drug in plasma. The time required for a medicine to be distributed from the plasma to the outermost region is the distribution stage. Drug levels established before reaching the end of a long phase of distribution may not reflect drug levels at sites of action.
Clearance – Elimination is either renal or non-renal (usually hepatic). Whereby, on the basis of serum creatinine or creatinine clearance, changes in renal clearance can be predicted, a routine liver function test for assessing liver medicine metabolism is not available. Clearance is independent of the drug dose or plasma concentration for most therapeutic drugs, which means that a change in the drug dose usually results in a proportional change in the plasma concentration. Needless to say, if clearance is dose-dependent (which is true for few drugs such as phenytoin, aspirin, and alcohol), a change in the dose may result in a disproportionate change in the plasma concentration, hence, it becomes difficult to select an effective therapeutic dose or to avoid toxicity.
Half-life – A therapeutics’ half-life relies on its volume of distribution and clearance. Half-life is defined as the period of time that it takes for the concentration or amount of a therapeutic in the body to decrease by 50%. Similar to clearance, for most therapeutics, the half-life is dose independent and does not change if the dose or the plasma concentration changes. The half-life determines how long it takes to achieve a steady-state concentration for a therapeutic after repeated dosing and how long it takes to eliminate that product from the body after dose cessation. In both situations, it takes 3-5 half-lives to achieve ~87.5–97% of the steady state concentration or to lose the same percentage after drug cessation. Patients with reduced drug clearance and consequently increased pharmacological half-life need longer time to reach a higher level of stable conditions. Generally speaking, as non-steady state drug concentrations are potentially erroneous and hard to interpret, most clinical monitoring in a constant state is recommended.
Protein binding of drugs – An evaluation of both protein-bound and free fractions of the drug’s concentration is a part of routine drug level analyses since the pharmacological activity depends on the free drug level. Changes in protein binding capacity for a drug may affect significantly the interpretation of reported levels for drugs with high protein-binding levels.For example, patients with uremia and hypoalbuminemia (renal dysfunction or hepatic impairment) have a marked decrease in drug-binding capacity which can results in a several fold increase in the drug plasma exposure. Another example is, if the ratio between free and total phenytoin (antiepileptic drug) concentration is increased, the usual therapeutic range is no longer applicable.
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