Multiple intravenous bolus dosing

If drug had been administered in equally sized multiple intravenous bolus doses at equally spaced t time intervals (e.g., t = 6 h), then an accounting of accumulated drug between doses must be instituted. Figure 1.18, similar to the zero-order input, shows that repetitive instantaneous dosing will produce an average Cp profile similar to Fig. 1.17. 

For multiple intravenous bolus doses, Cp in the nth dosing period is... 

Interestingly, unlike simple, classic competitive models, increasing drug concentration C will not overcome the inhibitor s effect Tol because Tol will increase proportionately—defeating the gains of increased drug concentration. This model has been used to simulate nicotine tolerance (61), multiple intravenous bolus dose morphine tolerance (64), and tolerance to caffeine s pressor effects (63). 

P. Veng-Pederson, Model-independent method of predicting peak, trough, and mean steady-state levels in multiple intravenous bolus dosing in nonlinear pharmacokinetics. / Pharm Sci 72 1098-1100 (1983). 

Figure 11.9 Plasma concenfration (Cp) versus time profile following the administration of multiple intravenous bolus doses of a drug, min, minimum max, maximum av, average t, dosing interval.

Notice that Eq. 12.43 includes two different dosing intervals tjv in the numerator and Xorai in the denominator Torai is the known interval for a satisfactory oral dosing regimen. In order to control fluctuation for the new multiple intravenous bolus dosing regimen, it is necessary to calculate a smaller (shorter) value for tiv and then insert this value into the numerator of Eq. 12.43. Since this means that the intravenous bolus will be given more frequently, and since (Cave)ss should... 

At this time, you are urged to consider the similarity between equations for a single intravenous bolus dose (Ch. 3) and multiple doses of intravenous bolus. You may notice an introduction of the term 1-e in the denominator. Otherwise, everything else should appear to be identical. 

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. 

But our work is still not done In order to use either Eq. 12.45 or Eq. 12.30, a value for fmax, the time to peak at steady state from our oral regimen, is needed. This is calculated from Eq. 12.7, for which we know values of the absorption and the elimination rate constants. Once the time to peak at steady state for the oral regimen is calculated, we can work our way backwards Tmax allows calculation of (Oss)orai by Eq. 12.45 or 12.30 then having a value of (Oss)orai allows Calculation of tjv by Eq. 12.44. Finally tiv can be inserted into Eq. 12.43 and the equation solved for the new multiple intravenous bolus maintenance dose, (Dm)iv-... 

As Schoenwald28 points out, the MDF is quite mobile in its application and can be applied to obtain two important concentrations in the design of controlled release delivery systems—Cp max and Cp min. Under multiple-dosing intravenous bolus input, applying MDF to Cp max and Cp mgives Eqs. (1.46) and (1.47) ... 

IFNp has been used in the treatment of multiple sclerosis. IFNp has been also used in combination with IFNy because of synergistic anti-tumor effects. The combinations of IFN appear to potentiate systemic effects and cumulative toxicity compared to administrahon of either interferon alone. Synergistic toxicity limits the tolerated dose maximum and may also limit efficacy. Low doses of IFN-p and -y given in combination, either by intravenous bolus or continuous infusion, do not appear to cause renal damage or dysfunction [62, 63]. 

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). 

Multiple dosing intravenous bolus administration Steady-slate plasma concentration... 

After thoracotomy and lobectomy, a 67-year-old male who had been administered a paravertebral catheter with continuous infusion plus multiple bolus doses of 20 mL 0.1% bupivacaine postoperatively developed tonic-clonic seizures and subsequent pulmonary aspiration. He was initially treated with intravenous (IV) midazolam and endotracheal intubation. Unforhmately the patient succumbed to aspiration pneumonitis and acute respiratory distress syndrome 3 days later in the intensive care xmit. 

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