Pharmacokinetic parameters area under curve

Further support for the thesis that the observed drug-membrane interaction directly or indirectly affects the receptor and does not represent pharmacokinetic influences can be derived from preliminary data of a small set of five derivatives for which some pharmacokinetic parameters were determined in rats [41]. The pharmacokinetic parameters - area under the curve (AUC), elimination rate constant (kd ), half-life (to 5), the time of maximal concentration (tmax), and maximal concentration (cmax) - did not correlate significantly with either log 1/ED50(MES), log Al/T2, or log fC0i t. Instead, even for this small set of compounds, log 1 /ED50(MES) correlated again significantly with both parameters log Al/T2 and log K ocL (r = 0.998 and 0.973 respectively). 

Test Items. As a rule, the pharmacokinetic parameters of test substances such as maximum concentration (Cmax) and time to reach maximum concentration (Tmax), area under curve (AUC), elimination half-life, clearance, distribution volume, bioavailability, etc., and pharmacokinetic nonlinearity are studied. The pharmacokinetics of metabolites of the test substance should be examined if necessary. 

PHARMACOKINETICS The area under the plasma concentration-time curve (AUC) was identified, in a preliminary analysis, as the important exposure covariate that was predictive of the safety biomarker outcome. Consequently, it became necessary to compare the distributions of AUC values across studies and dosage regimens. Figure 47.8 illustrates distributions of the exposure parameter AUC across studies. It is evident that AUC values are higher in diseased subjects than in healthy volunteer subjects at the same dose level. To adjust for the difference between the two subpopulations, an indicator function was introduced in a first-order regression model to better characterize the dose-exposure data. Let y be the response variable (i.e., AUC), X is a predictor variable, P is the regression coefficient on x, and e is the error term, which is normally distributed with a mean of zero and variance cP. Thus,... 

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... 

Thus, %F is defined as the area under the curve normalized for administered dose. Blood drug concentration is affected by the dynamics of dissolution, solubility, absorption, metabolism, distribution, and elimination. In addition to %F, other pharmacokinetic parameters are derived from the drug concentration versus time plots. These include the terms to describe the compound s absorption, distribution, metabolism and excretion, but they are dependent to some degree on the route of administration of the drug. For instance, if the drug is administered by the intravenous route it will undergo rapid distribution into the tissues, including those tissues that are responsible for its elimination. 

Pharmacokinetic parameters such as area under the concentration-time curve (AUC) and maximal plasma concentration can be predictive of treatment outcome when specific ratios of AUC or maximal plasma concentration to the minimum inhibitory concentration (MIC) are achieved. For... 

There is no experimental evidence available to assess whether the toxicokinetics of -hexane differ between children and adults. Experiments in the rat model comparing kinetic parameters in weanling and mature animals after exposure to -hexane would be useful. These experiments should be designed to determine the concentration-time dependence (area under the curve) for blood levels of the neurotoxic /7-hcxane metabolite 2,5-hexanedione. w-Hcxanc and its metabolites cross the placenta in the rat (Bus et al. 1979) however, no preferential distribution to the fetus was observed. -Hexane has been detected, but not quantified, in human breast milk (Pellizzari et al. 1982), and a milk/blood partition coefficient of 2.10 has been determined experimentally in humans (Fisher et al. 1997). However, no pharmacokinetic experiments are available to confirm that -hexane or its metabolites are actually transferred to breast milk. Based on studies in humans, it appears unlikely that significant amounts of -hexane would be stored in human tissues at likely levels of exposure, so it is unlikely that maternal stores would be released upon pregnancy or lactation. A PBPK model is available for the transfer of M-hcxanc from milk to a nursing infant (Fisher et al. 1997) the model predicted that -hcxane intake by a nursing infant whose mother was exposed to 50 ppm at work would be well below the EPA advisory level for a 10-kg infant. However, this model cannot be validated without data on -hexane content in milk under known exposure conditions. 

Exposure is represented by pharmacokinetic parameters demonstrating the local and systemic burden on the test species with the test compound and/or its metabolites. The area under the matrix level concentration-time curve (AUC) and/or the measurements of matrix concentrations at the expected peak-concentration time Cmax, or at some other selected time C(llme, are the most commonly used parameters. Other parameters might he more appropriate in particular cases. 

The term clearance is used here in the sense of total body clearance and is analogous to the term renal clearance. The body as a whole is regarded as acting as a xenobiotic-eliminating system, where the rate of elimination divided by the average plasma concentration of the compound is the total body clearance. Here clearance is calculated (25) by dividing the administered dose of the substance by the area under the plasma concentrationtime curve produced by that dose. This pharmacokinetic parameter, as well as others presented in this publication, was calculated by the use of the MLAB on-line computer system established at the National Institutes of Health by Knott and Reece (26). Similar to t the total clearance is a composite of the individual clearances of the material by the various tissues of the body. 

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. 

The pharmacokinetic information that can be obtained from the first study in man is dependent on the route of administration. When a drug is given intravenously, its bioavailabihty is 100%, and clearance and volume of distribution can be obtained in addition to half-life. Over a range of doses it can be established whether the area under the plasma concentration-time curve (AUC) increases in proportion to the dose and hence whether the kinetic parameters are independent of dose (see Figure 4.1). When a drug is administered orally, the half-life can still be determined, but only the apparent volume of distribution and clearance can be calculated because bioavailability is unknown. However, if the maximum concentration (Cmax) and AUC increase proportionately with dose, and the half-life is constant, it can usually be assumed that clearance is independent of dose. If, on the other hand, the AUC does not increase in proportion to the dose, this could be the result of a change in bioavailability, clearance or both. 

The blood concentration-time profile for a theoretical drug given extravascularly (e.g., orally) is shown in Figure 5.2. Some pharmacokinetic parameters, such as Cmax, T x> area under the curve, and half-life, can be estimated by visual inspection or computation from a con-... 

Compared to baseline saquinavir pharmacokinetic parameters obtained in period 1, the use of garlic reduced the mean saquinavir area under the concentration-time curve (AUC) by 51%, and the maximum (Cmax) and minimum (Cmin) saquinavir concentrations by 54% and 49%, respectively. After a 10-day washout, the AUC, Cmax, and Cmin values were within a range of 60% to 70% of baseline values. The magnitude of the decline in concentration might result in therapeutic failure and viral rebound in patients with HIV. Based on the pharmacokinetic parameters obtained in period 3, it also appears that garlic might have a prolonged, albeit lesser, effect on saquinavir exposure. The effects of combined treatment with other protease inhibitors that are also potent cytochrome P-450 (CYP) enzymes modulators need to be further evaluated. 

Drugs and toxicants with multi-exponential behavior depicted in Figure 6.14 require calculation of the various micro constants. An alternative method involves using model-independent pharmacokinetics to arrive at relevant parameters. Very briefly, it involves determination of the area under the curve (AUC) of the concentration-time profiles. The emergence of microcomputers in recent years has greatly facilitated this approach. 

In pharmaceutical research and drug development, noncompartmental analysis is normally the first and standard approach used to analyze pharmacokinetic data. The aim is to characterize the disposition of the drug in each individual, based on available concentration-time data. The assessment of pharmacokinetic parameters relies on a minimum set of assumptions, namely that drug elimination occurs exclusively from the sampling compartment, and that the drug follows linear pharmacokinetics that is, drug disposition is characterized by first-order processes (see Chapter 7). Calculations of pharmacokinetic parameters with this approach are usually based on statistical moments, namely the area under the concentration-time profile (area under the zero moment curve, AUC) and the area under the first moment curve (AUMC), as well as the terminal elimination rate constant (Xz) for extrapolation of AUC and AUMC beyond the measured data. Other pharmacokinetic parameters such as half-life (t1/2), clearance (CL), and volume of distribution (V) can then be derived. 

Figure 16 Changes to pharmacokinetic parameters over 13-week dosing regimen. (A) Maximum plasma concentration (Cmax) of DFP determined after single doses of 10, 30, or 100 mg/kg of DFP compared to the Cmax after 13 weeks of dosing. (B) AUC after a single dose of 10, 30, or 100 mg/kg of DFP compared with the Cmax after 13 weeks of dosing. Abbreviations DFP, [(5,5-dimethyl-3-(2-propoxy)-4-(4-methanesulfonylphenyl)-2(5//)-furanone)J AUC, area under the plasma concentrationtime curve. Source From Ref. 64.

Plasma caffeine and paraxanthine Descriptive pharmacokinetic parameters (standard parameters including peak concentrations (Cmax), time of Cmax (Tmax), area-under-the-curve (AUC) between time 0 and time t where t = 24 h post dose (AUCo-t), AUC after extrapolation to infinity (AUCo-co), apparent terminal half-life total clearance (CL)) for... 

The importance of tissue penetration varies with the site of infection. The CNS is one body site where the importance of antimicrobial penetration is relatively well defined and correlations with clinical outcomes are established. Drugs that do not reach significant concentrations in cerebrospinal fluid should either be avoided or instilled directly when treating meningitis. Apart from the bloodstream, other body fluids where drug concentration data are clinically relevant include urine, synovial fluid, and peritoneal fluid. Pharmacokinetic parameters such as area under the concentration-time curve (AUC) and maximal plasma concentration can be predictive of treatment outcome when specific ratios of AUC or maximal plasma concentration to the minimum inhibitory concentration (MIC) are achieved. For... 

A Level C IVIVC establishes a single-point relationship between a dissolution parameter, for example, T 50% dissolved in four hours and a pharmacokinetic parameter [e.g., 50% area under the curve (AUC), Cmax, Tmax]. A Level C correlation does not reflect the complete shape of the plasma concentration time curve, which is the critical factor that defines the performance of ER products. ... 

Another important parameter is the area under the plasma concentration-time curve (AUC). It reflects the extent of drug absorption. From a product quality aspect, knowledge of the described pharmacokinetic parameters is important. Utilizing these parameters, one would establish drug release characteristics of a tablet in vivo. 

Because stereoselective processes are species-related, the enantiomeric ratios of plasma concentrations at various times and areas under the plasma concentration-time curves may differ among animal species after the administration of a drug racemate. Chiral inversion, which occurs to a variable extent in different species, can be equivocally established only by administering individual enantiomers to the animal species of interest and measuring, using a sensitive stereospecific analytical method, the enantiomer administered and the optical antipode in biological fluids and tissues. The pharmacokinetic parameters based on plasma concentration-time data for each of the enantiomers can be statistically compared. 

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