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A typical pharmacokinetic profile represents a drug concentration in blood (or plasma or serum) over a period of time usually measured post drug administration until most of the drug is eliminated from the body. The shape of the plasma drug concentration–time profile depends on the route of administration of the drug. If the drug was administered intravenously, it becomes available in the systemic circulation instantly and the drug concentration is hypothetically at its maximum following its administration; this will gradually decline with time as the drug is eliminated from the body (Figure 2.2).

When the drug is administered into the tissues, for example, muscles (intramuscular injection) or taken orally (tablets, capsules, etc.), it has to go through a complex absorption process before it appears in the blood. Hence, there is a significant lag time to see the therapeutic effect of the drug compared to intravenous administration. This is one reason when the intravenous route of administration is preferred over the oral route in accidents or medical emergencies when a prompt response of a lifesaving drug is desired.

Figure 2.2 A typical pharmacokinetic profile (plasma drug concentration–time profile) of a drug following intravenous (IV) or oral administration.

Following oral administration of a drug, once the drug starts to be absorbed and appears in the blood circulation, its plasma concentration increases as a function of time. As soon as the drug starts to circulate in the blood, it leads to drug clearance (by metabolism and excretion). However, during the initial phase (termed as the absorption phase), the drug absorption surpasses the elimination leading to an increase in plasma drug concentration over time. A therapeutic response from the drug (for example a pain relief following analgesic drug) is observed when the drug concentration reaches the minimum thresholds required to produce the therapeutic effect, known as minimum effective concentration (MEC). The time taken for the plasma drug concentration to get to the MEC post administration is referred to as the onset time.

Following administration to sites other than intravenous, the plasma concentration reaches a plateau, termed as C_max or maximum plasma concentration of the drug; after this point, the elimination becomes dominant compared to absorption. The t_max refers to the time taken to get to the C_max from when the dose was administered. Following this point, the elimination surpasses the absorption leading to a net loss of the drug from the body and plasma drug concentration starts to decrease with time; this refers to the elimination phase. For drugs which are not absorbed efficiently from the gut, formulation strategies underpinning principles of biopharmaceutics can improve the drug absorption. Conversely, often a slower rate of absorption is beneficial in sustaining the drug effect for an extended period, for instance, modified release dosage forms (e.g., sustained‐release, slow‐release or controlled‐release). This often helps to reduce the dosage frequency of a drug and improves patient compliance. The pharmacokinetic profiles of such formulation exhibit a ‘flip‐flop’ model where there is significant drug absorption still taking place beyond C_max.

Figure 2.3 A typical pharmacokinetic profile (plasma concentration–time profile) following oral drug administration illustrating common pharmacokinetic parameters.

Pharmacokinetic studies help to determine the safe and effective dose of a drug by optimising the dose to keep the drug concentrations well above MEC but well below the minimum toxic concentration (MTC) that is also known as the maximum safe concentration (MSC). The concentration difference from MEC to MSC is referred to as the therapeutic window or the therapeutic index, shown in Figure 2.3. The wider the window, the safer is the dosage regimen. Where there is a narrow window, a much tighter dosage regimen is needed to ensure that fluctuations in the plasma drug concentration do not exceed the MTC or fall below the MEC. Drugs where the therapeutic window is very narrow are often referred to as NTI (narrow therapeutic index) or potent drugs (pharmacologically active at a very small dose) and require close monitoring (refer to Section 2.12) and often need personalised adjustment of dosages to prevent toxic adverse effects.

The term duration of action refers to the time period when drug concentration stays above the MEC threshold; hence, it represents the time period during which the drug remains therapeutically effective. The term AUC (area under the curve) refers to the total area under the plasma concentration–time profile and represents the total circulatory concentration of a drug over a period of time (Figure 2.3).