Constant rate infusion

An intravenous infusion involves a continuous flow of drug into a patient at a rate defined by the infusion rate constant, Rini, with units of mass/time. Discussions of infusion normally present the infusion rate constant as inf, which may be confused with a true reaction rate constant. Therefore, this presentation of infusion uses a less ambiguous variable, Rmi, for the infusion rate constant. 

The constant rate can be calculated from the concentration of drug solution and the flow rate of this solution, For example, the concentration of drug solution is 1% (w/v) and this solution is being infused at the constant rate of 10mLh (solution flow rate). So 10 mL of solution will contain 0.1 g (100 mg) drug. Hence, the units of the infusion rate, (constant rate) = solution flow rate (mLh ) X concentration (pgmL ), will be mass per unit time ( igh ). In this example, the constant infusion rate will be 10mLh multiplied by 100 mg/10 mL, or 0.1 g h (100 mg h ). 

If the drug is administered by a constant infusion rate (IR), the curve follows an unsteady function with zero-order kinetics (AClAt = const.) before the infusion is stopped (t < Tinfus) and first-order kinetics after cessation of infusion. Zero-order kinetics frequently can also be observed with diug absoiption where (KOabs = DR.) and (Tabs = Tinfus) hold true. 

Hence, the slope of the semilogarithmic plot of 1 - Cp tVC versus time t yields the transfer constant of elimination kp. From the known rate constant of infusion k, the transfer constant of elimination kp and a graphical estimate of one can then derive the plasma volume of distribution Vp, using the steady-state condition which has been derived above. 

The following data was obtained after the administration of a single 500-mg dose of a drug by slow intravenous infusion. Calculate the AUC, elimination rate constant, and the biological half-life of the drug. 

Using a simple one-compartment model, the loading dose and the infusion rate required to maintain a constant plasma concentration can be calculated as follows. 

A four-compartment model consisting of a two-compartment model for each enantiomer, with elimination from both compartments, connected by rate constants for chiral inversion was fitted to the concentration data, whereas the sedative effects were correlated with the blood concentrations of R- and S-thalidomide by means of logistic regression. PK modeling predicted that varying the infusion time of a fixed dose of S-thalidomide between 10 min and 6 h would have little influence on the maximal blood concentration of formed R-thaKdomide. These effects may chiefly be exerted by S-thalidomide, but the enantiomers are interconverted in vim... 

A steady plasma level can be achieved by giving the drug in a constant intravenous infusion, the steady-state plasma level being determined by the infusion rate, dose D per unit of time T, and the clearance, according to the equation n... 

A model based on the assumption that a metabolite is present within a single compartment with defined rate constants for absorption and elimination of the metabolite. The rate of appearance of a tracee and the infusion of tracer are assumed to take place in a single pool that is instantly well-mixed. Wolfe has described in detail how the constant tracer infusion method allows one to calculate half-life, pool size, turnover time, mean residence time, and clearance time. 

Nitroglycerin infusions Administer nitroglycerin IV and nitroglycerin in dextrose infusions only via an infusion pump that can maintain a constant infusion rate. Diabetes mellitus Use solutions containing dextrose with caution in patients with known subclinical or overt diabetes mellitus. 

A constant infusion rate must be maintained with an infusion pump in order to assure proper dosage control. Take care to... 

The rate constant for removal of I from the central compartment was 2.94 in the control runs and was decreased to 1.32 by infusion of thiamine at the lower rate the higher rate of infusion of thiamine... 

By setting the input function, I(t), in the differential equations on p. 28 to a constant rather than zero the equations can be solved to yield the disposition function for an intravenous infusion. With a fixed rate infusion, the plasma concentration will gradually increase towards a steady state concentration, CSS. Since CSS is constant, the amount of drug entering the body via the infusion at steady state must equal that being eliminated, (i.e. the clearance). Thus the infusion rate, R, e.g. mg min-1, needed to reach CSS is R=CSS.CI. It will take approximately 4 to 5 terminal half-lives to reach 95% CSS. Note that if the infusion rate is doubled CSS will also double, but the time taken to reach CSS remains the same, i.e. it is independent of the infusion rate (Figure 2.6). 

Extent and duration of action of various types of insulin as indicated by the glucose infusion rates (mg/kg/min) required to maintain a constant glucose concentration. The durations of action shown are typical of an average dose of 0.2-0.3 U/kg. The durations of regular and NPH insulin increase considerably when... 

Thus, the scalers on the dosimeter module may be set to display in mCi of Rb-82, since the circuit incorporates an adjustable pulse divider corresponding to the proportionality constant. In addition to displaying the activity of Rb-82 passing the detector at any instant, the second scaler provides a summation of total activity eluted. The flow rate constant, F, is set equal to the flow rate control of the infusion pump. 

Figure 19.5 Physiological pharmacokinetic model for hepatic uptake of drug constantly infused in the isolated rat liver perfusion system. Q, flow rate (mL/min) Cb, inflow concentration (pg/mL) Cs, sinusoidal concentration (pg/mL) Vs, sinusoidal volume (mL) X, binding constant (pg) Xm, maximum binding amount (pg) K, binding constant (mL/pg) kmt, internalization rate constant (min-1).

In contrast to noncompartmental analysis, in compartmental analysis a decision on the number of compartments must be made. For mAbs, the standard compartment model is illustrated in Fig. 3.11. It comprises two compartments, the central and peripheral compartment, with volumes VI and V2, respectively. Both compartments exchange antibody molecules with specific first-order rate constants. The input into (if IV infusion) and elimination from the central compartment are zero-order and first-order processes, respectively. Hence, this disposition model characterizes linear pharmacokinetics. For each compartment a differential equation describing the change in antibody amount per time can be established. For... 

The equations above apply strictly to dmgs administered as a single IV bolus dose, but for drug administered as an infusion or via oral route, or after multiple dosing, the calculation of AUMC must be adjusted to account for drug input [i. e., infusion time (T) or absorption rate constant JCa and extent of bioavailability F], as shown by Straughn [3]. Although, in theory, AUC will not be affected by the route, the AUMC will be overestimated, and this will result in an overestimation of Vss. 

All simulations were based on an IV bolus dose of 1000 mg, an infusion dose rate of 10 mg/h, and a Vc of 1 L. The micro rate constants used for the simulations were chosen to generate a family of bi-exponential curves with terminal half lives ranging from approximately 6 h to 3 days and exhibiting a fraction of drug eliminated by the tissue (flj) from approximately 30% to 99%. The parameters for 10 simulations are listed in Table 7.1. 

A first experiment to test the model predictions could be to replace the constant glucose infusion rate GIRq by a harmonically oscillating infusion rate [10] ... 

Since ke, CLt, and Vd are constant for most drugs showing linear kinetics, Css is directly proportional to R0, that is, the steady-state plasma concentration is directly proportional to the infusion rate. For example, if the infusion rate is doubled, the plasma concentration ultimately achieved at the steady state is doubled (Figure 2.2). Furthermore, the steady-state concentration is inversely proportional to the clearance of the drug, CLt. Thus, any factor that decreases clearance, such as liver or kidney disease, increases the steady-state concentration of an infused drug (assuming Vd remains constant). 

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