Steady-state plasma concentration fluctuation

The plasma concentration will continue to rise until it reaches a plateau, or steady state. At this time, the plasma concentration will fluctuate between a maximum (Cmav) and a minimum (CrnLn) level, but, more important, the amount of drug eliminated per dose interval will equal the amount of drug absorbed per dose. When a drug is given at a dosing interval that is equal to its elimination half-life, it will reach 50% of its steady-state plasma concentration after one half-life, 75% after two half-lives, 87.5% after three, 93.75% after four, and 96.87% after five. Thus, from a practical viewpoint,... 

With chronic use the plasma t) of lithium is 15-30 h. Lithium is usually given 12-hourly to avoid unnecessary fluctuation (peak and trough concentrations) and maintain a plasma concentration just below the toxic level. A steady-state plasma concentration will be attained after about 5-6 days (i.e. 5 x t) ) in patients with normal renal... 

An example of the results of a steady-state study, with dosing every 6 hr, is illustrated in Fig. 3. The pharmacokinetic data employed to generate the results shown in Fig. 3 were identical to those used for Fig. 2. The results demonstrate the influence of the rate and extent of absorption on the steady-state plasma concentrations. The lower plasma concentrations shown for product C reflect the lower extent of absorption for this product. Products A and B have the same extent of absorption, but differ in rate of absorption. Product A is more rapidly absorbed than product B, and thus there is a greater fluctuation between the maximum and minimum concentrations at steady state. 

For drugs with half-lives between 3 and 8h (Table 4.2), selection of the dosage interval must take into account the margin of safety of the drug, the range of therapeutic plasma concentrations, which indicates the degree of fluctuation in steady-state concentrations that would be acceptable, and the... 

If pharmacokinetics are dependent on dose or time, or a slow-release formulation is being studied, it is necessary to examine bioequivalence at steady state. For controlled-release formulations which are intended to produce relatively flat concentration-time profiles, an index of fluctuation is required, for example - Cn,jj])/C. A study at steady state may also be needed if the assay is not sensitive enough to quantify plasma concentrations of drug up to four half-lives after a single dose. Sometimes it is not technically feasible to assay a drug in plasma and it may then the justifiable to compare bioavailability by the total amount of drug excreted in urine, or pharmacodynamic data may be used, but these cases are exceptions. 

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. 

Figure 11.10 Plasma concentration (Cp) versus time plot illustrating high (a) and low (b) fluctuation () values following the attainment of the steady-state condition, min, minimum max, maximum MTC, minimum toxic concentration MEC, minimum effective concentration.

Drug fluctuation is the ratio of peak and trough plasma concentrations at steady state. 

The calculations in parts (f) and (g) support the theory that a smaller dose given more frequently will yield greater drug accumulation and smaller drug fluctuation, h. It has already been determined that administration of 300 mg aminophylline (equivalent to 237 mg theophylline), every 8h yields a peak steady-state theophylline plasma concentration of 14.44pgmL . The following equation allows determination of the loading dose (Di) necessary to attain this theophylline plasma concentration instantaneously. 

The use of oxymorphone ER has a series of potential advantages stemming from issues relating to clinical practicality, ease of use, as well as favorable pharmacodynamic and pharmacokinetic attributes. Oxymorphone ER has high analgesic uniformity, with minimal fluctuations in plasma concentration when dosed every 12 hours during steady state [2]. Such limited variation in the oxymorphone plasma concentration... 

The direct measurement of clearances normalized to body surface area and body water volume, expressed on a weekly basis, is crucial in the assessment of treatment adequacy. Creatinine and urea clearance are the most widely used adequacy indices in PD and APD. In a steady state, the calculation of clearance, that is, the ratio between dialytic (and renal) solute removal and blood solute concentration, requires quantitation of solute removed by total collection of drained dialysate. Blood and dialysate solute concentrations are measured by standard assays. The ratio of dialysate to blood solute concentration multiplied by the dialysate volume equals the clearance (Van Stone 1989). In APD, the intermittency or variable intensity of the therapy causes a modest compartmental disequilibrium with fluctuation of plasma concentrations between the predialytic (evening) and postdialytic (morning) values (Newman 1995, Calconi 1998). This difference is more marked for urea than for creatinine (Newman 1995). 

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