Area under the plasma concentration versus time

A. Area Under the Plasma Concentration Versus Time Curve... 

For compounds whose distribution fits more complex models, a more rigorous method uses the area under the plasma concentration versus time curve (AUC). Thus,... 

AUC area under the plasma concentration versus time curve. 

Tyrbing et al. [166] studied the stereoselective disposition of omeprazole and its formed 5-hydroxy metabolite in five poor metabolizers, and five extensive metabolizers of 5-mephenytoin. After a single oral dose of omeprazole (20 mg), the plasma concentrations of the separated enantiomers of the parent drug and the 5-hydroxy metabolite were determined for 10 h after drug intake. In poor metabolizers, the area under the plasma concentration versus time curve [AUC(0-8)] of (+) omeprazole was larger... 

PL2 - slope of placebo effect as a function of time (in days), Di - slope of drug effect as a function of AUC (24 h steady state), D2 - slope of drug effect as a fraction of the slope of placebo effect on time, E50 -drug effect that results in a 50% reduction in TSS, AUC - area under the plasma concentration versus time curve over 24 h at steady state calculated from individual predicted CL in the analysis. 

PK usually is expressed in several quantitative, clinically meaningful parameters, including half-life (T i2), area under the plasma concentration versus time curve (AUC), oral bioavail-abUity (F), volume of distribution (V ), clearance (CL), maximum observed plasma concentration (Cmax) tinic dose administration that Cmax occurs (T ax), and minimum concentration between successive doses (C i ). 

In bioavailability studies, the shape of and the area under the plasma concentration versus time curves are mostly used to assess rate t and extent (AUC) of absorption. Sampling points or periods should be chosen such that the concentration versus time profile is adequately defined to allow calculation of relevant parameters. For single-dose studies, the following parameters should be measured or calculated ... 

Midha KK, Hubbard JW, Rawson MJ. Retrospective evaluation of relative extent of absorption by the use of partial areas under the plasma concentration versus time curves in bioequivaience studies of conventional release products. European Journal of Pharmaceutical Sciences, 1996, 4 381-384. 

Another factor associated with the adverse effects of oxybutynin IR, especially in older patients, is the transient high peak serum oxybutynin plasma concentration and area under the plasma concentration-versus-time curve (AUC), which is twofold higher in elderly patients than in younger adults, after both single and multiple doses. Oxybutynin IR is best tolerated when the dose is gradually escalated from no more than 2.5 mg twice daily to start, to 2.5 mg three times daily after... 

Major descriptive PK parameters of exposure are peak concentration (Cmax), trough concentration (Cmin), area under the plasma concentration versus time curve (AUC), and bioavailability (F) as illustrated in the time-plasma concentration profile in Figure 3.1. Primary mechanistic PK parameters contributing to the extent of drug exposure are clearance (CL) and volume of distribution (Vdss). The ratio of Vdss-to-CL is the mean residence time (MRT), an intrinsic parameter that characterizes the residence time of drug molecules in the body. CL, Vdss, and MRT can be called dispositional PK parameters as well. Fraction absorbed (/(,), gut bioavailability (Fgut), and hepatic bioavailability (Fh) are the three major mechanistic parameters that control the total bioavailability (F). 

The area under the plasma concentration versus time curve, also called the area under the curve AUC), ends up being an extremely useful parameter in PK models. It can be used as a means of evaluating the volume of distribution (V) and total elimination clearance (CL), it can provide a measure of the bioavailability F) for extravascular drug delivery (see Section 10.9.4.4), and it provides a means to test the assumption of first-order linear elimination kinetics (as will be described in Section 10.15.8). As shown previously in Section 10.1.3.3, the AUC can be represented graphically as the area between the plasma concentration versus time curve and the horizontal axis, illustrated in Figure 10.24, or it can be written mathematically as... 

As discussed previously, the area under the plasma concentration versus time curve AUC) can be very useful in determining the bioavailability of a drug and other PK parameters. The AUC for the one-compartment IV infusion model is represented graphically as the shaded area in Figure 10.37. The value of AUC for this model can be calculated directly by the equation... 

Pharmacokinetic Analysis. Standard noncompartmental analyses were conducted to assess ATI and ATF pharmacokinetics using WinNonlin software (v. 2.1) (Pharsight, Mountain View, CA). The areas under the plasma concentration versus time curve from time zero to inhnity (AUCint) were determined via the log-linear trapezoidal method. The terminal half-life was determined from the relationship of ti/2 = In 2/, where k is the negative slope of the terminal phase of the InC versus time plot. Systemic clearance (CL) was estimated by dividing the administered dose by AUCint. The volume of distribution at steady state (Vss) was determined by the product of clearance and the mean residence time. 

Schaad - Lanyi et al. (1987) studied the pharmacokinetics of single oral doses of clofazimine over 11 days following administration. They examined the effect of food on the bioavailability. Following administration with food the area under the plasma concentration versus time curve (AUC) and the peak plasma concentration Cmax were 62 and 30% higher respectively compared to results obtained in the fasted state. The... 

Figure 12.4 Typical plasma concentration (Cp) versus time profile following the administration of many identical doses of a drug at an identical dosing interval by an extravascular route and the attainment of steady-state condition. AUC, area under the plasma concentration versus time profile r, dosing interval.

Pharmacokinetic parameters, such as elimination half life (ti/2), the elimination rate constant (K), the apparent volume of distribution (V) and the systemic clearance (Cl) of most drugs are not expected to change when different doses are administered and/or when the drug is administered via different routes as a single or multiple doses. The kinetics of these drugs is described as linear, or dose-independent, pharmacokinetics and is characterized by the first-order process. The term linear simply means that plasma concentration at a given time at steady state and the area under the plasma concentration versus time curve (AUC) will both be directly proportional to the dose administered, as illustrated in Fig. 15.1. 

Figure 15.1 Relationship between the plasma concentration (Cp) at a time at steady state (a) and the area under the plasma concentration versus time (ADC) curve (b) against the administered dose for a drug that exhibits dose-independent pharmacokinetics.

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