Intravenous bolus administration parameters

How the fundamental pharmacokinetic parameters of a drug are obtained following the intravenous bolus administration of a drug will be discussed below. These parameters, in turn, form a basis for making rational decisions about the dosing of drugs in therapeutics. The following assumptions are made in these discussions (Fig. 3.1) ... 

The kinetic parameters of the noncompartmental model are those defined previously for the accessible pool and system. However/ the formulas depend upon the experimental protocol/ especially on the mode of drug administration. In this chapter/ only the canonical inputs will be considered/ such as an intravenous bolus (or multiple boluses) or constant infusion (or multiple constant infusions). References will be given for those interested in more complex protocols. 

Items 16-18 A new drug was studied in 20 healthy volunteers to determine basic pharmacokinetic parameters. A dose of 100 mg was administered as an intravenous bolus to each volunteer and blood samples were analyzed at intervals as shown in the graph below. The average plasma concentrations at each time are shown by the solid circles at 10 and 30 minutes and at 1,2, 3, 4, 6, and 8 hours after administration. 

In order to determine this parameter, following the administration of a drug as an intravenous bolus, in theory, we would have to know the amount of drug in the body at a time and the corresponding plasma concentration. However, practically, it is easier to determine the apparent volume of distribution from the knowledge of initial plasma concentration (pgmL ) and the administered dose (mg or mgkg ). 

Therefore, it is a common practice to use values of the elimination rate constant, the elimination half life and the apparent volume of distribution obtained from intravenous bolus or infusion data to compute parameters associated with extravascular administration of a drug. 

The Rb-82 generator permits serial studies in the same patient as often as every 10 minutes with 20-60 mCi of Rb-82 for rapid bolus intravenous infusion. Inherent in the administration of high levels of Rb-82 activity is the need for precise flow control from an automated system to deliver the desired amount of radioactivity. The development of the alumina column parameters and the elution protocol as well as the automated microprocessor system controller are presented here. Some of the details of this system have been discussed in earlier publications (15,21). Generator produced Rb-82 is used as a diffusible flow tracer in myocardial perfusion studies and as a nondiffusible tracer in brain studies to assess blood brain barrier permeability changes in patients with brain tumors or Alzheimer s type dementia. 

Figure 30.6 shows a prediction of the plasma concentration of ARA-C and total radioactivity (ARA-C plus ARA-U) following administration of two separate bolus intravenous injections of 1.2 mg/kg to a 70-kg woman. All compartment sizes and blood flow rates were estimated a -priori, and all enzyme kinetic parameters were determined from published in vitro studies. None of the parameters was selected specifically for this patient only the dose per body weight was used in the simulation. The prediction has the correct general shape and magnitude. It can be made quantitative by relatively minor changes in model parameters with no requirement to adjust the parameters describing metabolism. 

In an open-label, crossover study in 18 healthy subjects, administration of heparin on day 5 of treatment with 40 mg of intravenous parecoxib twice daily for 6 days produced no clinically or statistically significant differences in coagulation parameters (PT, aPTT and platelet counts), when compared with heparin alone (bolus dose of heparin 4000 units then a 36-hour infusion of 10 to 14 units/kg). Use of these drugs together was well tolerated. However, prolongation of bleeding time was not assessed. ... 

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