Biopharmaceutics. Группа авторов

Area Under the Curve (AUC)

      The term AUC refers to the total area under the drug’s plasma concentration–time curve and represents the total circulatory concentration of a drug over a period of time, often also referred to as total exposure. It is usually expressed as either AUC_0–t (from the administration of dosage to the last point of measurement in pharmacokinetic profile) or AUC_0–∞ (from the administration of dosage to an infinite time when drug concentration reaches near zero).

      AUC is an important pharmacokinetic parameter which represents the extent of absorption of a drug from a dosage form and, therefore, helps in determining the bioequivalence of two dosage forms of the same drug or comparing an innovators’ product (brand) with a generic.

AUC can be estimated by geometrically calculating the area under the curve of a plasma drug concentration–time profile. This is usually done by dividing the curve into various small geometries such as trapezoids or rectangles and triangles to enable accurate measurements. This is shown in Figure 2.10. If the drug concentration is expressed as mg L⁻¹ against time in hours in a pharmacokinetic profile, then AUC is expressed as mg h L⁻¹

2.11 Bioequivalence

      The pharmacokinetic profiles of two products containing the same drug are often compared. Two formulations which give ‘essentially’ equivalent circulating concentrations of a drug at each point in time in a pharmacokinetic profile are likely to elicit equivalent therapeutic effects and therefore can be regarded as bioequivalent.

Bioequivalence studies are helpful to assess the pharmacokinetics of two drug products, for instance: originally formulated product versus a reformulated or modified drug product, two different dosage forms of the same product e.g., tablets versus oral liquid or comparison of the generic with innovator's original product. Biopharmaceutical considerations in early development help to achieve optimum absorption and bioavailability of a drug product or developing targeted delivery systems. The biopharmaceutical approaches in formulation design are discussed in detail in Chapter 8.

Figure 2.10 An illustration showing the calculation of AUC in a plasma drug concentration–time profile.

      Bioequivalence studies usually compare the C_max, t_max and AUC of the two products and if found within tolerances as set by the regulatory agencies (e.g., MHRA, FDA and EMA), the products may be declared as bioequivalent. Chapter 10 provides a detailed account of regulatory perspectives in bioavailability and bioequivalence studies.

2.12 Steady State

      Medicines are often not taken as just a single dose and repeat administration of dosages is often required to achieve remission. In chronic conditions, such as diabetes or hypertension, medicines are administered regularly to maintain the plasma concentration of drugs constantly within the therapeutic window to ensure maintenance of the therapeutic response. After multiple dosage administrations, when a pharmacokinetic equilibrium is achieved, the plasma concentration becomes constant (fluctuates in a constant pattern within the therapeutic window), termed as the ‘steady state’.

At the steady state, the rate of drug input into the systemic circulation becomes equal to the rate of drug output (elimination); hence, a pharmacokinetic equilibrium keeps a fairly constant level of drug concentration in the body. It takes about three to five half‐lives for a drug to get to the steady state (Figure 2.11). This may mean that a drug with t_½ = 8 h if taken twice a day will achieve a steady‐state plasma concentration in 40 hours (Box 2.6). For some drugs, this steady‐state plasma concentration needs very close monitoring during treatment for a patient, termed as therapeutic drug monitoring (TDM).

Figure 2.11 Repeat dose pharmacokinetic profile showing steady state compared to the first dose.

Box 2.6 How long it takes to get to the steady state?

      It takes about five half‐lives to get to the steady‐state concentration after administering multiple dosages of a drug.

Drug	Dosage interval, τ	Halt‐life, t½	Time to steady state,
Lignocaine	1 h	90 min	7.5 h
Theophylline	12 h (MR*)	8 h	40 h
Digoxin	24 h	48 h	10 days
Amiodarone	24 h	50 days	250 days

* modified release dosage form.

Therapeutic drug monitoring (TDM) involves frequent checking of the plasma drug concentration in the patient and consequent adjustment of the dose to ensure plasma concentrations are maintained within the desired therapeutic range. TDM is usually performed for drugs that are known to exhibit significant pharmacokinetic variability, those with a very narrow therapeutic range such as potent drugs or those where the pharmacological response strongly depends on maintaining a target drug concentration in the body (Box 2.7). Often such variability in pharmacokinetics is due to intra‐ and inter‐subject variability in drug absorption, metabolism or elimination processes. The differences in rate and extend of drug absorption (often due to physiological or formulations related factors) may have implications in steady‐state pharmacokinetics and can therefore affect therapeutic efficacy.

Box 2.7 Therapeutic drug monitoring (TDM).

Drug	Therapeutic range
Lithium	0.4–0.8 mmol L−1
Phenytoin	Скачать книгу В начало < 12 13 14 15 16 17 18 19 20 21 > В конец