Key Principles of Pharmacology

Based on data gathered during pharmacokinetic studies, Pharmacokinetics (PK), applying scientific and mathematical models helps to predict and understand the time course of Absorption, Distribution, Metabolism, and Excretion of medicines in the body.. This allows scientists to assess the relationship between the medicine’s beneficial and toxic effects, and to predict the safety and tolerability of the medicine in humans. Data gathered during pharmacokinetic studies are thus essential for determining dosing schedules in clinical trials. A favourable PK profile is vital to the therapeutic success of a medicine.  

Figure. 4: Concentration of medicine within blood plasma (Y axis) vs. time (X axis)   

If we give a person a medicine at time zero, we will see the concentration of the medicine go up and then fall slowly as it is eliminated from the body. In the first phase the medicine enters the body faster than it is being removed (absorption phase), and its concentration in the body increases to reach a maximum (Cmax.) at a certain time (Tmax.). Then, after the peak concentration has been reached, the medicine is eliminated from the body faster than it is entering, so the concentration of the medicine in the body starts decreasing (elimination phase).  

By plotting plasma concentrations of the medicine versus time, we can calculate the area under the curve (AUC (from time zero to infinity), expressed in units of μg x h/mL (μg × h/mL). Cmin in the graph may refer to the detection limit of the medicine, that is the minimum concentration measurable. Whenever the determination of AUC is partial (incomplete), the time period over which it is determined should be specified, for example, AUC0–12 h refers to area under the curve from time zero to 12h after administration. 

One further important parameter is the elimination half-life of a medicine, defined as the time it takes for the concentration of the medicine in the plasma or the total amount in the body to be reduced by 50% (T1/2 in the graph). In other words, after one half-life, the concentration of the medicine in the body will be half of the starting dose. With each additional half-life, proportionally less of the medicine is eliminated. However, the time required to reach half of the original concentration remains constant. In general, the medicine is considered to have a negligible therapeutic effect after 4 half-lives, that is, when only 6.25% of the original dose remains in the body. The elimination half-life is a useful pharmacokinetic parameter as it provides an accurate indication of the length of time that the effect of the medicine persists in an individual. It can also show if accumulation of the medicine is likely to occur with a multiple dosing regimen. This is helpful when it comes to deciding the appropriate dose amount and frequency. Along with other pharmacokinetic data and values about the individual patient, the half-life can help health practitioners to estimate the rate at which a drug will be eliminated from the body, and how much will remain after a given time period.  

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 the plasma.(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 types of 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 levels achieved 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. 

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). 

Pharmacodynamics (PD) is the study of the effect of a medicine on the body. 

There are two ways a medicine can affect the body: 

A medicine can change conditions within the body, or 

A medicine can interact with specific parts of the body on a cellular or sub-cellular level. 

The primary objective of pharmacodynamic studies is to gather information on how the medicine affects the body this can be biochemical, physiologic, and molecular effects and involves receptor binding (including receptor sensitivity), postreceptor effects, and chemical interactions).). It allows scientists to assess the efficacy of the medicine – that is, whether or not the medicine is having the desired effect on the target, and if so, how strong that effect is.  

It also allows a better understanding of the relationship between the concentration of the medicine in the body and the strength of its effect. This means that PK and PD both together influence dosing, benefit, and adverse effects (for example, addressed in PK/PD models). 

The majority of medicines either mimic or inhibit normal physiological/biochemical processes or inhibit pathological processes. 

Pharmacodynamics places particular emphasis on dose–response relationships, In principle, then the goal would be to dose for an optimal plasma concentration of the medicine for a desired level of response. In reality, there are many factors affecting this goal. Pharmacokinetic factors determine peak concentrations, and concentrations cannot be maintained with absolute consistency because of metabolic breakdown and excretory clearance. Genetic factors may exist which would alter metabolism or drug action itself, and a patient's immediate status may also affect indicated dosage. 

A simplified schematic of PK and PD parameters and their interrelation is given in the following figure (Fig. 6). 

Figure.6: Relationship between the plasma concentration – time curve obtained following a single extravascular (e.g. oral) dose of a medicine and parameters associated with the therapeutic or pharmacological response

Two parameters, as shown in the above figure, deserve specific mention because they give an indication of the efficacy and safety of the medication tested: 

The therapeutic window is the amount of a medication between the amount that gives an effect (minimum effective concentration) and the amount that gives more adverse effects than desired effects (maximum safe concentration). To note: adverse effects (side effects) of various nature can occur while the medicine is effective (benefit) but their influence (risk) must be less than the positive effect (a favourable benefit – risk ratio) over the range of intensity (from minimum effective concentration to Cmax) to make the medicine acceptable. Therefore, medication with a small therapeutic window must be administered with care and control, e.g. by frequently measuring blood concentration of the drug.