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3. Measuring Pharmaco*kinetics
3.1. Bioavailability
In order to understand and interpretpharmaco*kinetikmeasurements the concept ofbioavailabityshould be known. To note: Absorption and bioavailability are related concepts.
In Pharmaco*kinetics Made Easy (Birkett, 2009) defines bioavailability as:
"Bioavailability is the fraction of the dose which reaches systemic circulation as intact drug"
Other definitions are possible and perhaps even desirable. The flaw of most definitions is the tendency to ignore the possibility that drugs might get absorbed by other routes, and that serum concentration may not be the concentration of highest interest. For instance, the United States FDA defines bioavailability as "the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of drug action" and the European EMA simply defines it as “The extent to which an active ingredient is absorbed from a medicine and becomes available in the body”.
Determination of bioavailability
A few points upfront:
Bioavailabilty, the fraction of the administered dose which reaches the systemic circulation unchanged, is denoted by the letter f and, if expressed as percent (which is usually the case), by the letter F
Calculation is based on the assumption that there is a direct relationship between the concentration of drug in blood or plasma and the concentration of drug at the site of action.However, consider the possibility that circulating drug levels may misrepresent its availability to its target. (Example: as the only biologically active form of the medicine phenytoin is the free drug, the circulating protein-bound fraction (up to 90%) is not available to its site of action in the brain, even though it might be well-absorbed)
When a medicine is given orally, only part of the administered dose appears in theplasma.(Example: if 100 mg of a medicine are administered orally and 70 mg of this medicine are absorbed unchanged, the bioavailability is 0.7 or seventy percent)
Various factors may affect bioavailability, such as Pharmaceutical factors, Patient related factors, Route of administration, metabolism
The most common typesof human bioavailability studies are Plasma Level - Time Studies. Following the administration of a single dose of a medication, blood samples are drawn at specific time intervals and analysed for drug content.
Bioavailability is then calculated by comparing plasma levels of a drug given via a particular route of administration (for example, orally) with plasma drug levelsachieved by IV injection.However, the concentration of a drug given IV will be maximal at Time Zero, whereas the concentration of an orally administered drug will be maximal at a later time (depending on the rate of absorption). This is where the AUC comes into play (the area under the curve calculated by plotting plasma concentrations of the drug versus time). The AUC equals the total exposure to an API that the body receives. In brief, the mathematical concept of Dost's Law of Corresponding Areas (1972) relates the AUC of an IV dose to the AUC of an orally administered dose. If the area under the oral concentration curve covers 50% of the area covered by the IV curve, the law dictates that the drug is 50% bioavailable.
The bioavailability of the intravenous dose of any drug is by definition 100%. Hence, the bioavailability of all other formulations and routes of administration can be compared to this reference value as an absolute standard, and from this the equation forabsolute bioavailabilitycan be derived:
The absolute bioavailability then isthe dose-corrected area under the curve (AUC) non-intravenous divided by AUC intravenous. The equation for calculating the absolute bioavailability (denoted by the letterfor, if expressed in percent, byF), of a drug administered orally (tablet) is given below:
Bioavailability of a drug administered orally is the ratio of the area calculated for oral administration compared with the area calculated for IV injection.
Whereas absolute bioavailability compares the drug formulation to an IV dose,relative bioavailabilitycompares it to another similar non-IV formulation. One may be comparing two tablets, or a tablet to a suppository, or something similar.
A graphic representation of the associated plots for an IV and an oral drug administration is given in the following figure.
Fig. 5: Concentration vs. time graph of AUC of IV and oral administration of a medicine
In summary:
Bioavailability is the fraction of the dose which reaches systemic circulation intact
IV bioavailability is by definition 100%
"Absolute" bioavailability compares one non-IV route with IV administration.
"Relative" bioavailability compares one non-IV route or formulation with another (instead of using IV route as a reference).
Studies in early clinical development
