Administration extravascular

Fig. 39.9. Time courses of plasma concentration Cp in a one-compartment model for extravascular administration, with different contingencies of (a) the transfer constant of absorption k p, (b) the transfer constant of elimination kpt and (c) the volume of distribution Vp.

Two-compartment catenary model for extravascular administration with incomplete absorption... 

We reconsider the data used previously in Section 39.1.2 in the discussion of the two-compartment system for extravascular administration (e.g. oral, subcutaneous, intravascular). The data are truncated at 120 minutes in order to obtain a realistic case. It is recalled that these data have been synthesized from a theoretical model and that random noise with a standard deviation of about 0.4 pg T has been superimposed. 

Thus after 6 hours the semilog plot of Cp versus time shown in Fig. 10 becomes a straight line and kei can be determined from the slope. Therefore, the overall elimination rate constant for a drug may be accurately determined from the tail of a semilog plot of plasma concentration versus time following extravascular administration if ka is at least five times larger than kei. 

Simulation Simulations exploring the effect of the rate of absorption, bioavailability after an extravascular administration, and the rate of activation/inactivation of the anti-migraine effect were performed. To achieve a response rate of 60% at 2 h, the rate of absorption seems to play a minor role if bioavailability fractions of at least 0.2-0.3 can be achieved and kon is >0.081 ml/ng. At later times after administration, higher values of A0ff are associated with faster offset of the response. 

The absolute bioavailability of representative macromolecules following extravascular administration is shown in Table 32.9. It is apparent that... 

When a drug reaches the systemic circulation, either after intravenous administration or after absorption following extravascular administration, it can be distributed in the elements of blood (erythrocytes, etc.) or bind to plasma proteins. Blood transports the drug to different organs where it diffuses at different rates. The drug not bound to plasma proteins will diffuse in the extravascular compartments and tissues where it can then bind to other proteins or other tissue components. 

Figure 2.5 Stages in drug absorption from an extravascular administration site (stomach, small intestine, intramuscular injection). Only drug in solution is absorbed. If the rate of dissolution (K2) is less than the rate of absorption (K3) then the rate at which drug is released from the dosage form controls absorption. This permits modified or sustained-release formulations, but can also lead to bioequivalence problems.

The fraction of drug absorbed into the systemic circulation after extravascular administration is defined as its bioavailability. 

With extravascular administration (e.g., per os [PO oral], intramuscular [IM], subcutaneous [SC], inhalation), less than 100% of a dose may reach the systemic circulation because of variations in bioavailability. 

Absolute bioavailability is a measure of the true extent of systemic absorption of an extravascularly administrated drug. Along with clearance and volume of distribution, absolute bioavailability is one of the important parameters to characterize PK. Low bioavailability of a drug can be caused by incomplete dissolution when administrated as a solid, inability to permeate membranes, and metabolic instability (first-pass metabolism). Despite the importance of absolute bioavailability, it is not routinely assessed due to the cost and toxicology requirements for such a study in a conventional study design, which requires an intravenous reference. Safety issues may arise due to solubility limitation and toxicity associated with Cmax effect. As a result, it is necessary to conduct a preclinical toxicological study with an IV formulation to ensure adequate human safety and potential problem. Bioavailability determined from animal models is not always predictive of that in human. 

Serial drug concentrations following single dose extravascular administration of different doses given as a solution (not as a formulated tablet, capsule, etc.) at amounts low enough so as to not precipitate in the gastrointestinal tract. 

Another type of identifiability relates to a model that is identifiable but the parameters are not unique. The classic example of this is the 1-compartment model after extravascular administration assuming complete bioavailability... 

The time-course of plasma drug concentrations following extravascular administration is often irregular, and simple analytical solutions for calculating Af/C and AUMC, such as Equations (3.2-4) and (3.2-5), are not readily available. For these cases, numerical integration methods may be used to evaluate the integrals in Equations (3.2-1) and (3.2-2), such that ... 

The noncompartmental analysis of pharmacokinetic data after extravascular drug administration, when coupled with that of IV dosing, can yield additional relevant pharmacokinetic parameters, particularly regarding absorption processes. For example, the systemic availability F), which represents the net fraction of the drug dose reaching the systemic circulation after extravascular administration, is defined as ... 

Fig. 9.30. Time course of a drug at each site following an extravascular administration.

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. 

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