Pharmacokinetics

Pharmacokinetics, sometimes abbreviated as PK, (from Ancient Greek pharmakon "drug" and kinetikos "to do with motion"; see chemical kinetics) is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism. The substances of interest include pharmaceutical agents, hormones, nutrients, and toxins.

Pharmacokinetics includes the study of the mechanisms of absorption and distribution of an administered drug, the chemical changes of the substance in the body (e.g. by metabolic enzymes such as CYP or UGT enzymes), and the effects and routes of excretion of the metabolites of the drug. Pharmacokinetics is often studied in conjunction with pharmacodynamics, the study of a drug's pharmacological effect on the body.

ADME
Pharmacokinetics is divided into several areas including the extent and rate of absorption, distribution, metabolism and excretion. This is commonly referred to as the ADME scheme:


 *  A bsorption - the process of a substance entering the blood circulation.
 *  D istribution - the dispersion or dissemination of substances throughout the fluids and tissues of the body.
 *  M etabolism (or Biotransformation) - the irreversible transformation of parent compounds into daughter metabolites.
 *  E xcretion - the removal of the substances from the body. In rare cases, some drugs irreversibly accumulate in body tissue.

Elimination is the result of metabolism and excretion.

Pharmacokinetics describes how the body affects a specific drug after administration. Pharmacokinetic properties of drugs may be affected by elements such as the site of administration and the dose of administered drug. These may affect the absorption rate.

A fifth process, Liberation has been highlighted as playing an important role in pharmacokinetics:


 * Liberation - the process of release of drug from the formulation.

Hence LADME may sometimes be used in place of ADME in reference to the core aspects of pharmacokinetics.

Plasma concentration curves


Drugs injected intravenously are removed from the plasma through two primary mechanisms: (1) Distribution to body tissues and (2) metabolism + excretion of the drugs. The resulting decrease of the drug's plasma concentration follows a biphasic pattern (see figure).

Alpha phase: An initial phase of rapid decrease in plasma concentration. The decrease is primarily attributed to drug distribution from the central compartment (circulation) into the peripheral compartments (body tissues). This phase ends when a pseudo-equilibrium of drug concentration is established between the central and peripheral compartments.

Beta phase: A phase of gradual decrease in plasma concentration after the alpha phase. The decrease is primarily attributed to drug metabolism and excretion.

Additional phases (gamma, delta, etc.) are sometimes seen.

Metrics
The following are the most commonly measured pharmacokinetic metrics:

In pharmacokinetics, steady state refers to the situation where the overall intake of a drug is fairly in dynamic equilibrium with its elimination. In practice, it is generally considered that steady state is reached when a time of 4 to 5 times the half-life for a drug after regular dosing is started.

The following graph depicts a typical time course of drug plasma concentration and illustrates main pharmacokinetic metrics:

Analysis
Pharmacokinetic analysis is performed by noncompartmental or compartmental methods. Noncompartmental methods estimate the exposure to a drug by estimating the area under the curve of a concentration-time graph. Compartmental methods estimate the concentration-time graph using kinetic models. Noncompartmental methods are often more versatile in that they do not assume any specific compartmental model and produce accurate results also acceptable for bioequivalence studies.

Noncompartmental analysis
Noncompartmental PK analysis is highly dependent on estimation of total drug exposure. Total drug exposure is most often estimated by area under the curve (AUC) methods, with the trapezoidal rule (numerical integration) the most common method. Due to the dependence on the length of 'x' in the trapezoidal rule, the area estimation is highly dependent on the blood/plasma sampling schedule. That is, the closer time points are, the closer the trapezoids reflect the actual shape of the concentration-time curve.

Compartmental analysis
Compartmental PK analysis uses kinetic models to describe and predict the concentration-time curve. PK compartmental models are often similar to kinetic models used in other scientific disciplines such as chemical kinetics and thermodynamics. The advantage of compartmental over some noncompartmental analyses is the ability to predict the concentration at any time. The disadvantage is the difficulty in developing and validating the proper model. Compartment-free modeling based on curve stripping does not suffer this limitation. The simplest PK compartmental model is the one-compartmental PK model with IV bolus administration and first-order elimination. The most complex PK models (called PBPK models) rely on the use of physiological information to ease development and validation.

Bioanalytical methods
Bioanalytical methods are necessary to construct a concentration-time profile. Chemical techniques are employed to measure the concentration of drugs in biological matrix, most often plasma. Proper bioanalytical methods should be selective and sensitive. For example microscale thermophoresis can be used to quantify how the biological matrix/liquid affects the affinity of a drug to its target.

Mass spectrometry
Pharmacokinetics is often studied using mass spectrometry because of the complex nature of the matrix (often plasma or urine) and the need for high sensitivity to observe concentrations after a low dose and a long time period. The most common instrumentation used in this application is LC-MS with a triple quadrupole mass spectrometer. Tandem mass spectrometry is usually employed for added specificity. Standard curves and internal standards are used for quantitation of usually a single pharmaceutical in the samples. The samples represent different time points as a pharmaceutical is administered and then metabolized or cleared from the body. Blank samples taken before administration are important in determining background and insuring data integrity with such complex sample matrices. Much attention is paid to the linearity of the standard curve; however it is not uncommon to use curve fitting with more complex functions such as quadratics since the response of most mass spectrometers is less than linear across large concentration ranges.

There is currently considerable interest in the use of very high sensitivity mass spectrometry for microdosing studies, which are seen as a promising alternative to animal experimentation.

Population pharmacokinetics
Population pharmacokinetics is the study of the sources and correlates of variability in drug concentrations among individuals who are the target patient population receiving clinically relevant doses of a drug of interest. Certain patient demographic, pathophysiological, and therapeutical features, such as body weight, excretory and metabolic functions, and the presence of other therapies, can regularly alter dose-concentration relationships. For example, steady-state concentrations of drugs eliminated mostly by the kidney are usually greater in patients suffering from renal failure than they are in patients with normal renal function receiving the same drug dosage. Population pharmacokinetics seeks to identify the measurable pathophysiologic factors that cause changes in the dose-concentration relationship and the extent of these changes so that, if such changes are associated with clinically significant shifts in the therapeutic index, dosage can be appropriately modified. An advantage of population pharmacokinetic modelling is its ability to analyze sparse data sets (sometimes only one concentration measurement per patient is available).

Software packages used in population pharmacokinetics modeling include NONMEM, which was developed at the UCSF.

Ecotoxicology
Ecotoxicology is the study of toxic effects on a wide range of organisms and includes considerations of toxicokinetics and toxicodynamics.

Software
Academic licenses are available for most commercial programs.

Noncompartmental

 * Freeware: bear and PK for R
 * Commercial: EquivTest, Kinetica, MATLAB/SimBiology, Phoenix/WinNonlin, PK Solutions.

Compartment based

 * Freeware: ADAPT, Boomer (GUI), SBPKPD.org (Systems Biology Driven Pharmacokinetics and Pharmacodynamics), WinSAAM, PKfit for R.
 * Commercial: Imalytics, Kinetica, MATLAB/SimBiology, Phoenix/WinNonlin, PK Solutions, PottersWheel, SAAM II.

Physiologically based

 * Freeware: MCSim
 * Commercial: acslXtreme, Cloe PK, GastroPlus, MATLAB/SimBiology, PK-Sim, Simcyp, Entelos PhysioLab.

Population PK

 * Freeware: ADAPT, Boomer, PKBugs, Pmetrics for R.
 * Commercial: Kinetica, MATLAB/SimBiology, Monolix, NONMEM, Phoenix/NLME, PopKinetics for SAAM II, USC*PACK.

Simulation
All model based software above.
 * Freeware: Berkeley Madonna, MEGen.

Educational centers
Global centres with the highest profiles for providing in-depth training include the Universities of Buffalo, Florida, Gothenburg, Leiden, Otago, San Francisco, Tokyo, Uppsala, Washington, Manchester and University of Sheffield.