Multiple extravascular dosing

Fig. 15 Spreadsheet illustrating the calculation of plasma concentrations after multiple extravascular doses, calculated using Eq. (56).

Unlike intravascular dosage forms, in which a solution of drug is injected (usually by the intravenous route) into the systemic circulation, extravascular dosage forms are not immediately delivered into the systemic circulation. Extravascular dosage forms such as oral, intramuscular, subcutaneous and transdermal patches are meant to deliver dmg to the systemic circulation however, this systemic delivery is not instantaneous. Therefore, the pharmacokinetic equations require a term reflecting an absorption process. In order to understand multiple oral dosing, one... 

This expression, which relies on fairly rapid absorption such that each subsequent dose is administered in the post-absorptive phase, can be readily employed to determine the extent of accumulation following extravascular administration of a drug as long as dosing interval and the elimination rate constant of the drug are available. Note the similarity between Eq. 12.27 for multiple oral dosing and Eqs 11.29,11.33 and 11.34 for multiple intravenous bolus administration. 

Fig. 8. The time course of drug-concentration changes in plasma water after multiple extravascular drug administration when the body is considered as a single compartment, c, = drug concentration at time f, x — length of the dosing interval R =r number of doses administered.

Interleukin-2 Human recombinant lL-2 aldesleukin, proleukin des-alanyl-1, serine-125 human lL-2) differs from native lL-2 in that it is not glycosylated, has no amino terminal Ala, and has an Ser substituted for the Cys at amino acid 125. The potency of the preparation is represented in International Units in a lymphocyte proliferation assay such that 1.1 mg of recombinant lL-2 protein equals 18 million International Units. Aldesleukin has the following in vitro biologic activities of native lL-2 enhancement of lymphocyte proliferation and growth of lL-2-dependent cell lines enhancement of lymphocyte-mediated cytotoxicity and killer cell activity and induction of interferon-7 activity. In vivo administration of aldesleukin in animals produces multiple immunologic effects in a dose-dependent manner. Cellular immunity is profoundly activated with lymphocytosis, eosinophilia, thrombocytopenia, and release of multiple cytokines e.g., TNF-a, lL-1, interferon-7). Aldesleukin is indicated for the treatment of adults with metastatic renal cell carcinoma and melanoma. Administration of aldesleukin has been associated with serious cardiovascular toxicity resulting from capillary leak syndrome, which involves loss of vascular tone and leak of plasma proteins and fluid into the extravascular space. Hypotension, reduced organ perfusion, and death may occur. An increased risk of disseminated infection due to impaired neutrophil function also has been associated with aldesleukin treatment. 

The conceptual understanding of Eq. 10.21 is vital not only for the understanding of the theory and rationale behind the use of two infusion rates to attain and then maintain the desired plasma concentration of a drug but also for the understanding of calculations of loading dose and maintenance dose Dm) when dmgs are administered as an intravenous bolus and extravascularly in multiple doses (discussed in Ch. 11). 

It is also worth mentioning here that the pharmacokinetic parameters obtained following the administration of a single dose of a drug, intra-or extravascularly, may prove to be helpful while tackling some equations in multiple-dosing pharmacokinetics. This includes the intercepts of the plasma concentration versus time data, the systemic clearance and the absolute bioavailability of a drug, when applicable. 

The Dost ratio permits the determination of the amount and/or the plasma concentration of a drug in the body at any time t (range, t=0 to t — T) following the administration of the nth (i.e. second dose, third dose, fourth dose, etc.) dose by intravascular and/or extravascular routes. In other words, this ratio will transform a single dose equation into a multiple-dosing equation. 

Multiple dosing extravascular routes of drug administration... 

---