Key Principles of Pharmacology

3. Measuring Pharmacokinetics

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.  

Pre-clinical outcomes from doing PK are: 


  • Select compounds that have the maximum potential of reaching the target (PK) 

  • Select the appropriate route of administration to deliver the medicine 

  • Understand how the blood levels relate to efficacy (PK-PD) or toxicity (TK-TD) in order to select safe doses 

  • Decide on the frequency and duration of dosing in order to sustain medicine at target for disease modification 

  • Predict Human pharmacokinetics 

 

To measure the timeline of the medicine through the body, there are a few measurements that need to be undertaken and calculated: 


  1. The speed at which the medicine appears in the blood (plasma) and its concentration after administration are measured (absorption and distribution). 

  1. How the medicine changes over time (metabolism) and leaves the body (excretion) is measured. 

  1. How fast the medicine disappears as it is converted into metabolites and even secondary metabolites is calculated. 

 

The obtained values are plotted in a chart like the one shown in Figure 4.  

 

pcm_pharm_fig1 

 

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.  

The area under the curve (AUC) shows the total exposure to a medicine that the body receives (the shading under the graph). This is a function of how high the concentration of the medicine goes and how quickly it is excreted.