Time Course of Drug Concentration in Plasma

The velocity of absorption depends on the route of administration. The more rapid the administration, the shorter will be the time (tniax) required to reach the peak plasma level (Cmax), the higher will be the Cmax, and the earlier the plasma level will begin to fall again. 

All rights reserved. Usage subject to terms and conditions of license. 

Time Course of Drug Plasma Levels During Repeated Dosing (A) 

The area under the plasma level-time curve (AUC) is independent of the route of administration, provided the doses and bioavailability are the same (law of corresponding areas). The AUC can thus be used to determine the bioavailability F of a drug. The ratio of AUC values determined after oral and intravenous administrations of a given dose of a particular drug corresponds to the proportion of drug entering the systemic circulation after oral administration. Thus, 

The determination of plasma levels affords a comparison of different proprietary preparations containing the same drug in the same dosage. Identical plasma level-time curves of different manufacturers products with reference to a standard preparation indicate bioequivalence with the standard of the preparation under investigation. 

Uptake from stomach and intestines into blood 

The speed at which the steady state is reached corresponds to the speed of elimination of the drug. The time needed to reach 

---

The methodology to predict the time course of drug concentration in plasma after administration is well described and well accepted as a pharmacokinetic principle. Today, pharmacokinetic principles are used routinely to estimate and manage dosing of medications for their safe and effective use. Such knowledge is useful not only in designing clinical trials for a new molecular entity, but also in day-to-day clinical practice (Box 5.1). 

B. Vrijens, E. Tousset, R. Rode, R. Bertz, S. Mayer, and J. Urquhart, Successful projection of the time course of drug concentration in plasma during a 1-year period from electronically compiled dosing-time data used as input to individually parameterized pharmacokinetic models. J Clin Pharmacol 45 461-467 (2005). 

Time course of PHY concentration in plasma and brain was compared after 650 ptg/kg dose i.m. and oral and 100 pig/kg after i.v. administration as shown in Figure 5.5. BuChE activity in plasma and AChE activity in brain was also compared after these doses. The figure shows the pharmacokinetic and pharmacodynamic effects of PHY. PHY does not reach an effective concentration in the brain after oral administration because of its first-pass effect. However, it is an effective pretreatment drug after i.v. and i.m. routes of administration. 

The dose-concentration-effect relationship is defined by the pharmacokinetic and pharmacodynamic characteristics of a drug. Pharmacokinetics comprises all processes that contribute to the time course of drug concentrations in various body fluids, generally blood or plasma, that is, all processes affecting drug absorption, distribution, metabolism, and excretion. In contrast, pharmacodynamics characterizes... 

It must be kept in mind that the time course of drug concentrations in the hypothetical peripheral compartment, as inferred or construed from the mathematical analysis of plasma concentration data, may not exactly correspond to the actual time course of drug concentrations in any real tissue or organ. The peripheral compartments of pharmacokinetic models are, at best, hybrids of several functional physiological units. Theoretically, one can assign a compartment for each organ, as illustrated in Fig. 13.5. 

However, there are other major factors in determining the dosing regimen, such as the nature of the concentration-response relationship for both efficacy and toxicity (therapeutic window) and commercial/ compliance factors. There are additional reasons why caution should be applied in assuming an efficacy-time profile from a given plasma concentration-time profile. Some reasons why the time course of drug concentration and effect may differ are given in Table 5.1. 

In practice, however, it appears in most instances as technically impossible to estimate the actual amount of drug in the body. The usual approach is, therefore, to measure the concentration of the drug in samples of blood or plasma taken at various time intervals. In order to obtain a relationship which would describe the time course of drug-concentration changes in blood or plasma after an intravenous injection, equation (6) has to be divided by a term which represents the volume of fiuid in which the drug distributes itself—the apparent volume of distribution Va. We may then write ... 

Fig. 2. The time course of drug concentration changes in plasma water after an instantaneous intravascular injection when the body is considered as a single compartment. Cg = apparent initial concentration = drug concentration at time / Ijo% = biological half life.

Deconvolution Estimation of the time course of drug input (usually in vivo absorption or dissolution) using a mathematical model based on the convolution integral. For example, the absorption rate time course (i abs) that resulted in the plasma concentrations (c(t)) may be estimated by solving the following convolution integral equation for r abs... 

Ideally, the release of an ionizable compound from a sustained-release product should be programmed in accordance with the variation in physiological pH along different segments of the Gl tract. Thus, theoretically, the amount of the absorbed (uncharged) species and the plasma concentration can be kept approximately constant throughout the time course of drug release and action. 

Pharmacokinetics provides a rational framework for understanding how the time course of observable drug concentration (usually in plasma) is related to the dose. The principles of pharmacodynamics described in Chapter 18 provide a companion framework for understanding the relationship between concentration and response. However, these scientific disciplines are not enough to describe the time course of drug response, for two main reasons ... 

The models described in Chapter 18 that are used to relate steady-state plasma concentrations of drug to observed effects can also be applied to the time course of drug effects. 

In order to clarify the pharmacological difference between la,25(OH)2D3 and la,25(OH)2D4> we examined the time course of blood concentrations after oral administration of these drugs to rats and dogs by a radioreceptor assay (RRA). Honma et al. found that the plasma concentration of la,25(OH)2D4 showed longer T]/2, higher Cmax and AUC values than those of la,25(OH)2D3. The results are well explained by the stronger affinity of la,25(OH)2D4 for DBP than that of la,25(OH)2D3 (Table 4 and Table5). 

Under non-steady-state conditions, time courses of plasma concentration and effect may dissociate. Thus, to characterize fully the time course of drug action under nonsteady-state conditions, PK and PD have to be adequately linked to predict the relationship of PD effect vs. drug concentration in plasma. This link is provided by the following four attributes in the integrated PK/PD models. 

Zero-order kinetics describe the time course of disappearance of drugs from the plasma, which do not follow an exponential pattern, but are initially linear (i.e. the drug is removed at a constant rate that is independent of its concentration in the plasma). This rare time course of elimination is most often caused by saturation of the elimination processes (e.g. a metabolizing enzyme), which occurs even at low drug concentrations. Ethanol or phenytoin are examples of drugs, which are eliminated in a time-dependent manner which follows a zero-order kinetic. 

Figure 39.4a represents schematically the intravenous administration of a dose D into a central compartment from which the amount of drug Xp is eliminated with a transfer constant kp. (The subscript p refers to plasma, which is most often used as the central compartment and which exchanges a substance with all other compartments.) We assume that mixing with blood of the dose D, which is rapidly injected into a vein, is almost instantaneous. By taking blood samples at regular time intervals one can determine the time course of the plasma concentration Cp in the central compartment. This is also illustrated in Fig. 39.4b. The initial concentration Cp(0) at the time of injection can be determined by extrapolation (as will be indicated below). The elimination pool is a hypothetical compartment in which the excreted drug is collected. At any time the amount excreted must be equal to the initial dose D minus the content of the plasma compartment Xp, hence ...

---