Area under the curve, AUC

Once the steady-state concentration is known, the rate of dmg clearance determines how frequendy the dmg must be adininistered. Because most dmg elimination systems do not achieve saturation under therapeutic dosing regimens, clearance is independent of plasma concentration of the dmg. This first-order elimination of many dmgs means that a constant fraction of dmg is eliminated per unit time. In the simplest case, clearance can be deterrnined by the dose and the area under the curve (AUC) describing dmg concentration as a function of total time ... 

Area under the Curve (AUC) refers to the area under the curve in a plasma concentration-time curve. It is directly proportional to the amount of drug which has appeared in the blood ( central compartment ), irrespective of the route of administration and the rate at which the drug enters. The bioavailability of an orally administered drug can be determined by comparing the AUCs following oral and intravenous administration. 

One solution to the volume problem was proposed using moment analysis. The steady-state volume of distribution (Vss) can be derived from the area under the curve (AUC) and the area under the first moment curve (AUMC). 

The effect of hemodialysis can be derived from the removed fraction (FR) that is the relative amount eliminated from the body during the time (/HD) of one dialysis session. This fraction can be derived from the half-life on dialysis (Tl/2on) or from the area under the curve (AUC) on and off dialysis. 

Analysis of most (perhaps 65%) pharmacokinetic data from clinical trials starts and stops with noncompartmental analysis (NCA). NCA usually includes calculating the area under the curve (AUC) of concentration versus time, or under the first-moment curve (AUMC, from a graph of concentration multiplied by time versus time). Calculation of AUC and AUMC facilitates simple calculations for some standard pharmacokinetic parameters and collapses measurements made at several sampling times into a single number representing exposure. The approach makes few assumptions, has few parameters, and allows fairly rigorous statistical description of exposure and how it is affected by dose. An exposure response model may be created. With respect to descriptive dimensions these dose-exposure and exposure-response models... 

The concentration-time curve can be integrated numerically and yields the so-called area under the curve (AUC) ... 

The area under the curve AUC is obtained by integrating the plasma concentration function between times 0 and infinity. This integral can be obtained analytically from eq. (39.16) ... 

The simplest non-compartmental parameter that can be obtained from the time course of the plasma concentration is its area under the curve AUC (see also Section 39.1.1) ... 

This parameter can be obtained by numerical integration, for example using the trapezium rule, between time 0 and the time T when the last plasma sample has been taken. The remaining tail of the curve (between T and infinity) must be estimated from an exponential model of the slowest descending part of the observed plasma curve ((3-phase) as shown in Fig. 39.15. The area under the curve AUC can thus be decomposed into a tmncated and extrapolated part ... 

From the mean residence time MRT, the area under the curve AUC and the administered dose D, one can derive the steady-state volume of distribution of... 

While carboplatin has the same mechanism of action as cisplatin, it has a much less toxic side-effect profile than cisplatin. The pharmacokinetics of carboplatin are best described by a two-compartment model, with an a half-life of 90 minutes and a terminal half-life of 180 minutes. Carboplatin is eliminated almost entirely by the kidney by glomerular filtration and tubular secretion. Many chemotherapy regimens dose carboplatin based on an area under the curve (AUC), which is referred to... 

Bioavailability was assessed from measurement of the area under the curve (AUC) of whole blood lead concentration vs time (Blood AUC) or from measurements of the lead concentrations in bone, kidney or liver (the arithmetic mean of the three tissues is shown in the table). Data are from Casteel et al. (1997) and EPA (1996a, 1996b, 1996c). 

The interaction of /2-hexane with toluene and trichloroethylene has also been examined in volunteers (Baelum et al. 1998). Exposure in these experiments was via a gastric feeding tube at controlled rates equivalent to what the authors stated would be delivered to the liver by inhalation exposure at Danish occupational exposure limits (50 ppm /7-hexane. 50 ppm toluene, and 30 ppm trichloroethylene). Coexposure to toluene and trichloroethylene slightly increased the area under the curve (AUC) representing concentration versus time for end exhaled /2-hexane air concentration, but urinary excretion of 2,5-hexanedione was unchanged. The only statistically significant interaction observed with /2-hexane was an 18% decrease in the urinary excretion of hippuric acid, a toluene metabolite. 

In the absence of target organ toxicity with which to set the high dose at the maximally tolerated dose, the high dose can be set at the dose that produces an area under the curve (AUC). This is 25-fold higher than that obtained in human subjects. 

In addition, treatment of animals with phenobarbital not only increased overall rates of metabolism and clearance, but also shifted the metabolite patterns. One of the more common methods used for determining an exposure to (or the amount of a metabolite produced) is to determine an area under the curve (AUC) for the metabolite. Further, one of the more common methods for representing a racemically preferred metabolite is to calculate the ratio of the R to the S. For example, the 3-decholoro metabolite of ifosfamide was produced in higher amounts from the R enantiomer while the 2-decholorometabolite was the major metabolite produced from the R enantiomer in naive animals. Treatment with phenobarbital shifted the metabolism so that the 3-dechloro metabolite was no longer the major metabolite for the S enantiomer. 

Demonstrate that the semi-log plot makes the curve more linear during its rise and fall from baseline. The recirculation hump is still present but is discounted by measuring the area under the curve (AUC) enclosed by a tangent from the initial down stroke. This is the AUC that is used in the calculations. 

A number of parameters such as, e.g., renal clearance, basal oxygen consumption (metabolic rate), area under the curve (AUC), maximum metabolic velocity, or cardiac output correlate to the body weight to the power of 0.75 Further support for the power of 0.75 comes from a more... 

The interindividual variability reflects differences in the extent of exposure, in toxicokinetics as well as in toxicodynamics. The variability due to factors which influence the extent of exposure (physiological differences in the intake, e.g., inhalation rates) can be considered by means of suitable parameters for the internal exposure (absorbed dose, area under the curve AUC, plasma concentration) if sufficient information is available. With respect to toxicokinetic factors, interindi-vidual differences in the metabolism of chemicals are generally considered as the most significant explanatory factor. Hardly any knowledge is available with respect to the factors that influence toxicodynamics. In the following, a brief overview of the factors playing a role for the toxicokinetic and toxicodynamic differences is presented. 

Hattis et al. (1987) examined the variability in key pharmacokinetic parameters (elimination half-lives (Ty ), area under the curve (AUC), and peak concentration (C ax) in blood) in healthy adults based on 101 data sets for 49 specific chemicals (mostly drugs). For the median chemical, a 10-fold difference in these parameters would correspond to 7-9 standard deviations in populations of normal healthy adults. For one relatively lipophilic chemical, a 10-fold difference would correspond to only about 2.5 standard deviations in the population. The authors remarked that the parameters studied are only components of the overall susceptibility to toxic substances and did not include contributions from variability in exposure- and response-determining parameters. The study also implicitly excluded most human interindividual variability from age and diseases. When these other sources of variability are included, it is likely that a 10-fold difference will correspond to fewer standard deviations in the overall population and thus a greater number of people at risk of toxicity. 

Area under the curve (AUC) is of decisive importance for the effect under consideration. Relative absorption is known or a similar absorption can be assumed. 

Absorption - Atier ora administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10 mg dose of ezetimibe to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax)- The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection. Ezetimibe has variable bioavailability the coefficient of variation, based on intersubject variability, was 35% to 60% for area under the curve (AUC) values. 

Fig. 6. The profile plots of the eight samples. The peak of each plot represents the relative density of the band in each rectangle. The larger the area under the curve (AUC), the higher the intensity of the band.

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