Modeling single dose

The potential for normal brain tissue injury is one of the limiting factors in the use of XRT for brain tumors. Pentobarbital is a cerebral radioprotectant in rodent and primate models after single doses, but is associated with significant risks. Of alternative barbiturates, thiopental given to tats receiving 70-Gy (7000-rad) whole-brain irradiation in a single fraction enhances the 30-day survival similarly to pentobarbital, whereas ethohexital and phenobarbital show no radioprotective activity (250). 

FIGURE 11.16 Control dose-response curve and curve obtained in the presence of a low concentration of antagonist. Panel a data points. Panel b data fit to a single dose-response curve. SSqs = 0.0377. Panel c data fit to two parallel dose-response curves of common maximum. SSqc = 0.0172. Calculation of F indicates that a statistically significant improvement in the fit was obtained by using the complex model (two curves F = 4.17, df=7, 9). Therefore, the data indicate that the antagonist had an effect at this concentration. 

Fig. 39.4. (a) One-compartment open model with single-dose intravenous injection of a dose D. The transfer constant of elimination (excretion and metabolism) is kp - (b) Time course of the plasma concentration Cp and of the contents in the elimination pool Xp. 

Fig. 39.7. (a) Two-compartment catenary model for extravascular (oral or parenteral) administration of a single dose D which is completely absorbed. The transfer constant of absorption is (b) Time courses of the amount in the extravascular compartment Xa, the concentration in the plasma compartment Cp and the content in the elimination pool X. ... 

The effect of incomplete absorption is that only a fraction of a single-dose D is made available to the central plasma compartment. The solution of the previous model needs, therefore, to be modified by replacing the term D by F D. Consequently the area under the curve AUCg under incomplete extravascular absorption will be smaller than the maximal AUC that results from complete absorption. The latter, as we have seen is equal to the AUC obtained from a single intravenous injection, which we denote by AUC,. These considerations can be summarized as follows ... 

In the previous discussion of the one- and two-compartment models we have loaded the system with a single-dose D at time zero, and subsequently we observed its transient response until a steady state was reached. It has been shown that an analysis of the response in the central plasma compartment allows to estimate the transfer constants of the system. Once the transfer constants have been established, it is possible to study the behaviour of the model with different types of input functions. The case when the input is delivered at a constant rate during a certain time interval is of special importance. It applies when a drug is delivered by continuous intravenous infusion. We assume that an amount Z) of a drug is delivered during the time of infusion x at a constant rate (Fig. 39.10). The first part of the mass balance differential equation for this one-compartment open system, for times t between 0 and x, is given by ... 

In the case of a one-compartment open model with single-dose intravenous administration, the mean residence time is simply the inverse of the elimination transfer constant kp, since according to the above definition we obtain ... 

Population PK analysis following a single dose of 30 mg microencapsulated octreotide acetate intramuscularly the PK profile of microencapsulated octreotide acetate was effectively described by the derived population model. The relationship between IGF-1 and drug concentration could be used to guide optimization of therapeutic octreotide dosage regimens... 

Although a single dose of ginseng has little acute effects, chronic dosing (twice daily, 5 days) reduces anxiety in behavioral models (open-field... 

Rnally, pharmacokinetic and pharmacokinetic/pharmacodynamic modelling can be used for the purpose of prediction of the concentration-time profile of the drug and drug-carrier conjugate after repeated administration from single dose data, as well as for the prediction of the dose needed to maintain the concentration at the target site within a therapeutic window. 

When mmor data are used, a POD is obtained from the modeled mmor incidences. Response levels at or below 10% can often be used as the POD. The POD alone, being a single-point estimate of a single dose-response curve, does not convey all the critical information present in the data from which it is derived. To convey a measure of uncertainty, the POD should be presented as a central estimate with upper and lower bounds. The POD for extrapolating the relationship to environmental exposure levels of interest, when the latter are outside the range of observed data. 

With regard to the characteristics of single-dose usage, some drugs fit well with Ainslie s model. Whereas for most people the delights of icecream eating diminish rapidly, the euphoria of a heroin injection lasts... 

---