Area under curve drug-concentration time curves

In Eq. (3.4), doseiv is the amount of drug administered intravenously, AUC is total area under the drug concentration-time curve, and k is the first-order elimination rate constant... 

Cl plasma concentration at time zero fi/2a, distribution half-life f1/2jg, elimination half-life Kej, elimination rate constant from central compartment Ki2/.K2i, transfer rate constant between peripheral and central compartments AUC(o ), total area under plasma drug concentration time curve Vd(area> apparent volume of distribution GB, total body clearance. 

Absolute bioavailability of a drug is the systemic availability of the drug after extravascular administration of the drug and is measured by comparing the area under the drug concentration-time curve after extravascular administration to that after IV administration, provided the and Vd are independent of the route of administration. Extravascular administration of the drug comprises routes such as oral, rectal, subcutaneous, transdermal, nasal, etc. 

AUC area under the drug concentration-time curve... 

Bioavailability is the amount of drug in a formulation that is released and becomes available for absorption or the amount of the drug absorbed after oral administration compared to the amount absorbed after intravenous administration (bioavailability - 100%), judged from areas remaining under plasma drug concentration-time curves. 

The significance of P-gp, however, in affecting absorption and bioavailability of P-gp substrate drugs can be seen in studies in knockout mice that do not have intestinal P-gp. The gene responsible for producing that protein has been knocked out of the genetic repertoire. Those animals evidenced a sixfold increase in plasma concentrations (and AUC, area under the plasma concentration-time curve) of the anticancer drug paclitaxel (Taxol) compared to the control animals [54]. Another line of evidence is the recent report... 

The answer is e. (Hardman, p 21J The fraction of a drug dose absorbed after oral administration is affected by a wide variety of factors that can strongly influence the peak blood levels and the time to peak blood concentration. The Vd and the total body clearance (Vd x first-order fte) also are important in determining the amount of drug that reaches the target tissue. Only the area under the blood concentration-time curve, however, reflects absorption, distribution, metabolism, and excretion factors it is the most reliable and popular method of evaluating bioavailability... 

The area under the plasma-concentration time curve, the AUC, is a useful parameter in defining fhe overall body exposure to a drug this parameter integrates the concentration-over-time fimction ... 

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 clinical development stage comprises three distinct components or phases (I, II, and III), and culminates in the filing of the NDA/MAA. Each phase involves process scale-up, pharmacokinetics, drug delivery, and drug safety activities. During phase I clinical development, the compound s safety and pharmacokinetic profile is defined. The determination of maximum concentration at steady state (Cmax), area under the plasma concentration time curve (AUC), elimination half-life, volume of distribution, clearance and excretion, and potential for drug accumulation is made in addition to studies that provide estimates of efficacious doses. Dose levels typically... 

Since the area under the plasma concentration-time curve (AUC) for a drug is a measure of the total amount of a drug reaching the general circulatory system, the bioavailability of a drug may also be defined in terms of the AUC as ... 

Figure 10 Plasma concentrations of a drug following a multiple-dosing regimen, of fixed dose and interval, intravenously (top) and orally (bottom). Note that in both cases the area under the plasma concentration-time curve within a dosing interval at plateau is equal to the total area following a single dose. Source From Ref. 1.

For a drug that is eliminated exclusively by the liver and that is completely absorbed following oral administration, the intrinsic clearance can be related to the area under the plasma concentration-time curve (AUCp0) if the well-stirred model of hepatic elimination is assumed (81,82) ... 

The intrinsic kinetic properties of the victim drug also influence the potential clinical consequences of an interaction. For orally administered medications that undergo significant presystemic extraction, impairment of clearance by a CYP inhibitor may produce increases in bioavailability (reduced presystemic extraction) as a consequence of reduced clearance. The effects may be particularly dramatic for CYP3A substrates (such as triazolam, midazolam, or buspirone) that undergo both hepatic and enteric presystemic extraction. As an example, coadministration of the CYP3A inhibitor ketoconazole with triazolam produced very large increases in area under the plasma concentration-time curve... 

The bioavailabilify of a drug formulation is best described by Cmax/Tmax (rate) and Area under the systemic concentration-time curve AUC (extent). 

However, drug substances for which /a may be affected by active transport processes [e.g., the efflux transporter P-glycoprotein (P-gp)] may require further model characterization to prevent misclassification of their permeability class. For example, functional expression of efflux transporters must be determined in cultured human or animal epithelial monolayers. At this time, the FDA recommends limiting the use of non-human permeability test methods to drug substances whose absorption is controlled by passive mechanisms. When applying the BCS, an apparent passive mechanism may be inferred when one of the following conditions is satisfied (i) a linear pharmacokinetic relationship between dose and a measure of bioavailability (e.g., area under the plasma concentration-time curve, AUC) is demonstrated in humans ... 

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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