Zero-order absorption models delivery

Zero-order absorption occurs when drug enters the systemic circulation at a constant rate. An IV infusion, in which a drug solution is delivered directly into the systemic circulation at a steady flow rate, represents an idealized zero-order absorption case. Because of this, standard zero-order absorption models are typically called IV infusion models and are designed specifically for the IV infusion case. This particular section deals with the one-compartment IV infusion model, so as in the previous one-compartment bolus IV model, the body is modeled as a single compartment with the implication that the distribution process is essentially instantaneous. As with the other standard models, the exact meaning of the assumptions inherent in this model are described next. Model equations then are introduced that allow the prediction of plasma concentrations for drugs with known PK parameters, or the estimation of PK parameters from measured plasma concentrations. Modification of the one-compartment IV infusion (zero-order absorption) model to approximate other types of steady drug delivery are described in Section 10.8.5. 

The standard one-compartment IV infusion (or zero-order absorption) model makes three inherent assumptions about the ADME processes that occur during and after drug delivery ... 

Three special cases are considered for the one-compartment zero-order absorption model. First is the extension of the IV infusion equations to cover steady extravascular drug delivery. Second is the use of the one-compartment zero-order absorption model to approximate the plasma concentrations of drugs that follow two-compartment kinetics. The last case... 

The two-compartment zero-order absorption model is more complex and harder to work with than the one-compartment zero-order absorption model. Thus the one-compartment model is often used when it provides a reasonable approximation to the two-compartment values. In fact, the one-compartment model is often used even when a drug is known to significantly deviate from single compartment kinetics. Just as in the case of the two-compartment bolus IV injection model in Section 10.10.5.3, as a general rule of thumb the one-compartment model can be employed with reasonable accuracy as long as < 2 82- When this simplification is used, the one-compartment IV infusion equations in Section 10.8 can be used without modification for an IV infusion, or with the modifications listed in Section 10.11.5.1 for steady extravascular delivery. 

The two-compartment model scheme is applied to the steady delivery of drug into the systemic circulation (zero-order absorption) in this section. The only difference between the instantaneous absorption and zero-order absorption two-compartment models is in the type of drug absorption. Thus all descriptions of what is included in each compartment, the use of micro and hybrid rate constants, and the different types of distribution volumes are identical to the two-compartment bolus IV model values. As was done previously for zero-order absorption, the model equations are written specifically for the case of IV infusion, with modifications for other types of zero-order absorption described in Section 10.11.5. 

The buccal permeability of the non-steroidal antiinflammatory drug, diclofenac sodium, has been evaluated in a dog model. The dog was selected because of the similarity of its buccal mucosa to that of man. Analysis of the buccal data indicated that diclofenac sodium permeability followed an essentially zero-order kinetic process with a minimal lag phase. Permeability of the drug was estimated to be 3 mg/cm2.h but significant differences were observed between animals. The absorption rate with the transbuccal delivery device decreased with time whereas the corresponding rate with a saturated solution was constant. This difference was attributed to the time dependency of drug delivery from the device and was modeled on the basis of release from a membrane-dispersed monolith combined with constant buccal permeability. The predictions of the model showed excellent agreement with the experimental data. 

The mathematical description of the absorption rate can be quite complex, depending on the level of detail included in the mathematical analysis. However, the goal here, as it is for most PK modeling, is to keep the mathematics as simple as possible while maintaining sufficient details to adequately describe the process. It turns out that the absorption rate for most drug delivery routes can be accurately approximated as either instantaneous, zero-order, or first-order absorption. The meaning and application of each of these types of absorption is described in the following sections. 

Itwas previously discussed in Section 10.7.5.1 that under certain circumstances, a zero-order drug delivery process of short duration can be approximated as an instantaneous absorption process. The conditions under which this approximation gives reasonable results can be investigated mathematically using model simulations. These simulations are made by keeping the total absorbed dose FD = F- ko- T) the same in each simulation. As illustrated in Figure 10.39, the instantaneous absorption model provides a reasonable approximation when T < This criteria can be employed as a... 

As shown previously for the one-compartment case, the two-compartment model for steady (zero-order) drug delivery can be approximated by a two-compartment instantaneous absorption model as long as the drug delivery period (T) is relatively short compared to the elimination half-life ty eUm)- As a general rule, the instantaneous model can be employed with reasonable accuracy as when T < tiy eUm- For cases where this simplification applies, the two-compartment bolus IV model equations can be used by simply replacing with F-h-T. 

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