Minimum plasma concentration at steady state

In the post-absorptive phase (i.e. as the term approaches zero), Eq. 12.14 becomes  

The above equation allows us to calculate the trough steady-state plasma dmg concentration for multiple oral dosing. 

The minimum, or trough, plasma concentration following the administration of a single, or the first, dose is obtained as follows  

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Cmin,ss Minimum plasma concentration at steady state fu Fraction unbound in plasma... 

Cmin.ss is the minimum plasma concentration at steady state fa is the fraction absorbed in man ... 

Estimation of the potency can be made in a several ways and will be highly dependent on the nature of the target. If a purified system is used it is normal to correct for the effect of plasma protein binding (which can be measured directly in human plasma) as it is usual for the effect to be proportional to the unbound concentration [82]. This can be used to set a value for the minimum plasma concentration at steady state. 

Equations 11.13 and 11.14 permit determination of the minimum or trough plasma concentration at steady state. A careful examination of the equation clearly suggests that the minimum or trough plasma concentration for a dmg is influenced by the initial plasma concentration, the elimination rate constant and, more importantly, the dosing interval. Since the administered dose is identical and the elimination rate constant is a constant, the minimum plasma concentration at steady state is influenced only by the dosing interval. 

Administration of an identical dose of a dmg more frequently (i.e. a smaller t value) will yield a higher minimum plasma concentration at steady state. Conversely, administration of the same dose of a dmg less frequently (i.e. a greater t value) will yield a smaller minimum plasma concentration at steady state. 

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... 

Equation 11.35 indicates that when N is small (i.e. dosing is more frequent), the range of dmg concentrations is smaller (i.e. the difference between the maximum and minimum plasma concentrations, at steady state, will be smaller). 

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 ... 

Minimum or trough plasma concentration at steady state against the number of administered doses. 

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). 

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. 

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. 

Figure 10.10 Predicted or theoretical plasma concentration (Cp) versus time profile following the administration of a drug as an intravenous bolus loading dose (DJ immediately followed by an infusion at rate Q. MTC, minimum toxic concentration MEC, minimum effective concentration ss, steady state.

The proximity between the values of the "average" steady-state concentration and the arithmetic mean of the maximum and the minimum plasma concentrations at infinity is solely... 

Plasma concentrations should be obtained at steady state, usually after a minimum of 1 week at constant dosage. Sampling should be done during the elimination phase, usually in the morning, 12 hours after the last dose. Samples collected in this manner are comparable for patients on once-daily, twice-daily, or thrice-daily regimens. 

The minimum plasma concentrations of roxithromycin at steady state (days 4-11) ranged from 3.22 to 3.69 mg/1 with 150 mg b.i.d. and from 2.02 to 2.22 mg/1 with 300 mg q.d. These results indicate that roxithromycin exhibited nonlinear kinetics and may involve a saturable process as evidenced by increased elimination rates and lack of dose proportionality between doses [25]. The nonlinear kinetics is most probably explained by saturation of roxithromycin serum protein binding... 

Figure 11.4 Plasma concentration (Cp) versus time profile following the administration of an identical intravenous bolus dose of a drug at an identical dosing interval (t). Please note that the steady-etate (ss) peak plasma concentrations are identical. Similarly, the steady-state plasma concentrations at any given time after the administration of a dose are identical, min, minimum max, maximum.

For drugs administered intravenously, the maximum and minimum steady-state plasma concentrations will occur at f=0 and t—r, respectively, following the administration of many doses (i.e. n is large). Equation 11.11 may be used to determine the steady-state maximum and minimum plasma concentrations as follows ... 

In Eq. 11.13, the term (Cp ) or (CpJ represents the minimum or trough plasma concentration of a drug at steady-state condition (i.e. following the administration of many doses and when time since the latest dose, t, is equal to t). Since Eq. 11.12,... 

Thus, a comparison of "average" concentration, minimum concentration and maximum plasma concentrations of a drug following the administration of the first dose and at steady state provides an insight into the extent to which a dmg would be expected to accumulate upon multiple-dosing administrations. 

The accumulation factor (R) following the administration of a drug by an extravascular route can be calculated by comparing the minimum plasma concentration of drug at steady state with the minimum plasma concentration following the first dose ... 

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,... 

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