What Are Pharmacokinetics Studies?

What is pharmacokinetics?

Pharmacokinetics (PK) is best described as the study of the time-lapse of an investigational products’ absorption, distribution, metabolism, and excretion. The relation between dose, plasma concentrations, and therapeutic or toxic effects, where this is feasible, should be studied.

PK studies are essential to establish therapeutic schedules, evaluate their relevance, or proceed to dosage adjustments in patients. Data obtained from such studies are useful for the design and conduct of subsequent clinical trials.  

What is clinical pharmacokinetics?

Applied clinical pharmacokinetic studies are performed to examine the absorption, distribution, metabolism, and excretion in healthy volunteers and/or patients.  

In PK clinical studies, subjects are given a single dose or repeated doses of an investigational product. Then, blood and/or urine samples are collected in compliance with a fixed schedule. Fecal samples may also be necessary. Then, the concentration of the investigational product and its metabolites are measured in these samples and the PK profile is evaluated. The rate of absorption and elimination should be estimated, and the results should be utilized for the determination of optimal points for sample collection.

In some instances, pharmacokinetic studies may be impossible or limited, e.g. where it would create risks for test subjects; in these cases, the use of the investigational product is partly or completely based upon pharmacodynamic and clinical trials.

The clinical pharmacokinetic methodology consists on:  

• choice of administration (route, dosage, dosage intervals),  
• choice of subject (healthy volunteers, patients with relevant disorders, patients with other interfering conditions),  
• choice of methodology (sampling and analysis, data processing, and statistics).

What factors affect pharmacokinetics or what are the four processes of pharmacokinetics?

Pharmacokinetic factors to be studied deal with:

• Absorption: absorption studies should be conducted using the route of administration that will be used clinically. Information on changes in blood levels of the investigational product is necessary, regardless of the route of administration.
• Distribution: volume of distribution should be calculated on the basis of the investigational product concentration changes in the circulation of human subjects.
• Metabolism: the pathway and ratio of metabolism should be assessed by measuring an investigational product and its metabolites in blood, urine, and, if necessary, feces. Major enzymes and those subtypes responsible for the metabolism of the investigational product should be determined.  

• Elimination: information on the urinary excretion (rate and extent) of an investigational product and its metabolites should be obtained. Fecal excretion should also be determined whenever necessary. When evaluating fecal excretion, consideration should be also given to the possibility that unabsorbed investigational product may appear in the feces.

PK studies Classification

There are two ways to evaluate the clinical pharmacokinetics of an investigational product: a "standard pharmacokinetic study," and a "population pharmacokinetic study."  

• Standard pharmacokinetic study: evaluates the PK profile of the investigational product by a single-dose or a repeated-dose study, under strictly managed conditions, following a defined protocol.  

• Population pharmacokinetic study: evaluates PK profiles by utilizing the blood concentration data obtained from a clinical study with the primary objective of determining the efficacy and safety of an investigational product.  

A decision to adopt either of the methods should be based on the objectives of the study and the stage of product development. It seems important to elaborate on the type of PK study based on the dosage regime:

• Single-dose study: the concentration of an investigational product and its metabolites are measured in blood following a single administration to healthy volunteers and/or patients. Furthermore, the amount and composition of the investigational product and its metabolites in blood, urine, and, when necessary, feces are measured to evaluate mass balance.  

Other variables to consider are:

• Plasma protein binding (identity of binding proteins and the unbound ratio),  

• bioavailability,  
• linearity of pharmacokinetics,  
• and the effects of meals  

The initial dose should be determined by referring to data from toxicity studies, toxicokinetic and nonclinical pharmacokinetic studies, as well as to results from previously conducted metabolic studies with human tissues, properties of pharmacologic actions, and, if available, clinical studies conducted abroad.  

Usually, a small number of healthy subjects are recruited for the study, and the dosage is increased, starting with the lowest dose, while monitoring any occurrence of adverse events.  

In order to evaluate the relationship between dosage and pharmacokinetic parameters, several doses should be used, including the estimated clinical dose and a dose higher than the estimated highest clinical dose. In a study involving patients, evaluating not only the relationship between dosage and blood concentrations but also that between blood concentrations and pharmacologic effects may provide valuable information.

• Repeated-dose study: the changes in pharmacokinetic parameters, confirmation of steady-state concentrations, and the potential for the accumulation should be evaluated when an investigational product is given repeatedly, according to the dosing route and schedule planned for clinical practice. The results should be compared with changes in blood concentrations estimated from the single-dose study results.  

The degree of changes in pharmacokinetic parameters depending on the administered dose and frequency of dosing should be evaluated with respect to the dose and the dosing regimen intended for clinical use.  

The appropriate number of subjects should be determined based on the results of single-dose studies. The frequency of sampling after the first administration should be that enabling the evaluation of pharmacokinetic profiles in subjects.  

What’s the PK study process

Pharmacokinetic studies play a pivotal role in informing the design of dosage regimens. Performing these studies involves several steps, including the approval of the study by an ethics committee, an appropriate study design, which includes determining the required sample size and study power, blood sampling strategies, and the analysis of blood samples.

Population pharmacokinetic study designs often include pharmacokinetic screening methods such as the single-trough screen, multiple-trough screen, and full screen. The choice of methods is based on the dosage form, feasibility, and whether the outcome of the study conforms to the study objectives. Representative values of pharmacokinetic parameters of the population (e.g., mean), factors that affect pharmacokinetics, the degree of the effects, and inter-and intra-individual variability can be obtained from a population analysis that is appropriately planned and implemented.

What is bioavailability in pharmacokinetics

For investigational product that show efficacy via the systemic circulation, pharmacokinetic parameters such as the absorption ratio, bioavailability, and absorption rate should be estimated. In cases of oral administration, comparison with results from intravenous administration is useful in order to estimate the absorption ratio and bioavailability, and to clarify the extent of first-pass effects.

Pharmacokinetic models

Developing pharmacokinetic models to inform dosing traditionally required several consecutive blood samples to be taken from each patient in order to describe the investigational product concentration versus the time curve. The development of population pharmacokinetic modeling approaches has overcome the limitations of traditional pharmacokinetic studies. Population pharmacokinetic models use concentration-time points from a number of clinical subjects to determine the pharmacokinetics of the investigational product in that population and can be designed to use the minimum number of samples possible from each patient 

Determining the optimal times for blood sampling also assists in minimizing the number of interventions required.

Food effect on pharmacokinetics

As absorption from the gastrointestinal tract is likely to be affected by meals, the effects of a meal on gastrointestinal absorption should be evaluated for investigational products that are administered orally. In such cases, a final formulation must be used. In the case of investigational products that are intended to be used locally, absorption from the application sites should be investigated using a final formulation.

Characteristics and degree of metabolism in the small intestine should be taken into consideration whenever an investigational product is administered orally and metabolized by some enzymes that are found in the small intestine in significant amounts.

Population and sample types in a PK study

An appropriate number of subjects should be used to determine the inter-individual variability of drug effects. A sufficient number of samples should be obtained at appropriate time points to estimate the blood concentrations of the product. However, consideration should be given to ethical and medical concerns regarding excessive blood collection. Urine samples should be collected until the unchanged drug and its metabolites are no longer detectable. When fecal excretion plays a significant role in the pharmacokinetics of a given product, the amount should also be studied.

When conducting studies, due consideration should be given to individual variation, and an appropriate number of volunteers should be used. The influence of frequent blood collection on the volunteers should also be considered.

With a population pharmacokinetic approach, usually, a large number of subjects participate in the study, while the number of samples collected from each subject can be small. The advantages of this approach include less inconvenience and stress on the subjects involved. This approach is considered suitable for special populations such as the elderly and children.  

The sample size should be appropriate and sufficient for the study objectives, population characteristics, dosage forms, and feasibility. It is important to record the time of administration and sample collection accurately.

To maximize the information obtained from the population pharmacokinetic approach, study procedures including the timing and number of samplings, methods for handling specimens, and data analysis methods must be appropriately planned.