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 Cmax or maximum plasma concentration of the drug; after this point, the elimination becomes dominant compared to absorption. The tmax refers to the time taken to get to the Cmax 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 Cmax.
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).
2.4 Bioavailability
The absorption of a drug at the administration site is a complex interplay between the physicochemical characteristics of the drug and the physiology of the surrounding tissues.
The drug absorption through the gastrointestinal tract, for instance, is a function of drug's solubility (Chapter 4), its dissolution (Chapter 6) within the gastrointestinal milieu and drug's permeability across the gastrointestinal mucosa (Chapter 5) taking into account the complex gastrointestinal anatomy and physiology (Chapter 11).
The fraction of the administered dose of a drug that reaches the systemic circulation is termed the Bioavailability (F) which is a function of the fraction that permeates through the gastrointestinal mucosa (fa), the fraction that survives gut‐wall metabolism during absorption (fg) and the fraction which escapes the hepatic metabolism (fh) when it passes through the liver. Figure 2.4 summarises various factors associated with drug absorption through the gastrointestinal tract. The fraction absorbed (fa) from the gastrointestinal tract is an interplay between physicochemical properties of the drug, its solubility and dissolution rate within the gastrointestinal luminal fluids and its stability in the gastrointestinal milieu (acidic/basic pH, the digestive enzymes, and the interaction with food and its digestive products). The fraction absorbed also depends on a drug's ability to cross the gastrointestinal absorptive barrier which in turn also depends on its physicochemical characteristics, lipophilicity, the partition coefficient and its susceptibility to various influx or efflux transporters present within gastrointestinal absorptive cells. The absorption of most of the drugs administered into the gastrointestinal tract, is, therefore, a complex phenomenon; hence, the oral bioavailability (F) is rarely equal to 1 (or 100%). In contrast, if the drug was administered into the blood circulation directly, such as intravenously (injected into the veins), it bypasses the absorption barriers and entirety of the administered dose is available in the systemic circulation, hence bioavailability (F) is 1.
The science of biopharmaceutics is invaluable to understand the complex interplay between physicochemical properties of the drug and gastrointestinal physiology to develop innovative formulations and drug delivery systems (Chapter 8) to improve the drug absorption and bioavailability through various routes of administration.
Figure 2.4 Physicochemical and physiological factors affecting the absorption of the drug from the gastrointestinal tract following oral administration.
2.5 Drug Distribution
The blood circulates ‘around the body’ (termed distribution) to various tissues and provides oxygen and nutrients, and also removes metabolic waste from the tissues;