Average plasma concentration at steady state

CaVjs Average plasma concentration at steady state... 

Because the area under the plasma drug concentration-time curve during a dosage interval at steady-state is equal to the total area under the curve after administering a single intravenous dose, the average plasma concentration at steady-state can be estimated from... 

Regardless of the route of drug administration, the "average" plasma concentration at steady state is influenced by the dose administered, the fraction of the administered dose that reaches the general circulation (for extravascular routes), the systemic clearance of the drug and the chosen dosing interval. 

For example, calculated or reported value of R = 2 simply suggests that the peak plasma concentration at steady state will be twice the peak plasma concentration for the first dose. Analogously, the minimum plasma concentration at steady state will be two times as high as the minimum plasma concentration for the first dose. An R value of 2 also means that the "average" plasma concentration at steady state will be twice the "average" plasma concentration for the first dose. This is applicable for an intravenous bolus of dmg. Therefore, knowledge of the calculated or reported R value permits prediction of the... 

Fluctuation (O) is simply a measure of the magnitude of variation in, or the differences between, the peak and trough plasma concentrations at steady state or, by some definitions, the peak and "average" plasma concentrations at steady state. 

Fluctuation, therefore, is simply a measure of the ratio of the steady-state peak or maximum plasma concentration to the steady-state minimum or trough plasma concentration of a drug or the ratio of the peak or maximum steady-state concentration to the "average" plasma concentration at steady state for the chosen dosage regimen. 

By comparison of maximum concentroHon at steady state with "average" plasma concentration at steady state... 

Fig. 1. Relationship between the VKORCl —1639 G>A genotype, plasma. S -warl arin concentration, and INR response.. S -warl arin plasma concentrations at steady-state are graphed for each of the VKOR Cl —1639 G>A genotypes. All subjects were stabilized with an INR between 2.0 and 3.0. Mean dose (mg/d) and average plasma concentrations for each of the groups are as follows VKORCl -1639 AA (n = 8) 2.7 mg/d, 0.48 mg/L VKOR Cl -1639 GA (n = 23) 4.3 mg/day, 0.54 mg/L and VKOR Cl —1639 GG (n = 29) 6.7 mg/d, 0.73 mg/L. Data originally published in Zhu Y, Sherman M, Reynolds KK, et al. Estimation of warfarin maintenance dose based on VKORCl (—1639 G>A) and CYP2C9 genotypes. Clin Chem 2007 53(7) l 199-205.)...

It should be noted that the "average" plasma concentration, obtained by employing Eqs 11.15 or 11.17, is neither the arithmetic nor the geometric mean of maximum and minimum plasma concentrations at infinity. Rather, it is the plasma concentration at steady state, which, when multiplied by the dosing interval, is equal to the area under the plasma concentration-time curve (AUC)o (i.e. from f=0 to t r). 

Therefore, in this example, if the subsequent doses are administered at a 24 h interval (i.e. dosing interval equals one half life of the drug), the peak steady-state concentration, the trough steady-state concentration and the "average" steady-state concentration will be twice the corresponding plasma concentration for the first dose. Is it accurate to say that if the peak plasma concentration at steady state is twice the peak plasma concentration for the first dose then the dosing interval represents the half life of the drug ... 

It may take a long time and the administration of many doses (over seven or eight) before the desired "average" steady-state drug concentration is attained. Therefore, an intravenous bolus loading dose (DJ may be administered to obtain an instant steady-state condition. The calculated loading dose should be such that that, at time t after its administration, the plasma concentration of drug is the desired minimum plasma concentration at steady state, that is ... 

The appropriate equation (see also Eq. 11.17 and Eq. 12.19) for average total (bound plus free) plasma drug concentration at steady state is ... 

Table 16.5 The effect of a change in free fraction on average total and free plasma for intravenous administration of the drugs in Table 16.4 drug concentrations at steady state ...

What would be the average plasma concentration of drug at steady-state if it is known that the plasma concentration at zero time point is 48 meg/ mL when 50 mg of the dose is given every 12 hours, and the elimination rate constant of the drug is 0.173 hour 1 ... 

Substitute for oral nicardipine - The IV infusion rate required to produce an average plasma concentration equivalent to a given oral dose at steady state is shown in the following table ... 

At steady state, by definition the total drug clearance, or loss, is equal to drug input and plasma concentration oscillates around an average figure. However two situations occur which can provide problems in dosing. 

Fluvoxamine increases clozapine plasma concentrations (34,35). In 16 patients taking clozapine monotherapy, fluvoxamine 50 mg was added in the hope of ameliorating the negative symptoms of schizophrenia (36). At steady state the serum concentrations of clozapine and its metabolites increased up to five-fold (average two- to three-fold). However, adverse effects were almost unchanged in frequency and severity, in spite of the pharmacokinetic interaction. 

During continuous intravenous infusion at an average rate of 41 ig/kg/ minute to 31 subjects, a mean steady-state plasma concentration of 2.2 pg/ ml was reported norketamine and dehydronorketamine attained mean peak plasma concentrations of 1.1 pg/ml and 0.7 pg/ml, respectively, in about 3 hours the subjects awoke at an average plasma concentration of 0.64 pg/ml (J. Idvall et al., Br. J. Anaesth., 1979, 51,1167-1173). Following an intramuscular injection of 0.5 mg/kg to 6 subjects, peak plasma concentrations of 0.10 to 0.43 pg/ml (mean 0.24) were attained in about 0.3 hour norketamine attained a mean peak plasma concentration of 0.09 pg/ml at about 1 hour (J. A. Clements et al., J. pharm. Sci., 1982, 71, 539-542). 

The ratio of the AUCs of the lactone and total topotecan appears to be relatively constant and averages about 0.3, which means that only 30% of the total drug concentration in the plasma represents the closed-ring lactone form. The distribution volume at steady state is 25-751/m, indicating extensive binding to tissues. Erythrocjdes act as a depot for topotecan (lactone), with steady-state concentrations almost 1.7 times those obtained in plasma. 

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