Maximum plasma concentration at steady state

Since the right side of Eq. 12.9 is always positive, it is apparent that the maximum plasma concentration at steady state occurs at an earlier time than that following the administration of a single dose. Furthermore, the time at which the maximum plasma concentration is observed following the first dose (i.e. t ax) is often the time at which the plasma is sampled after the administration of subsequent doses to assess peak plasma concentration. Mathematical principles clearly suggest that this would not be a sound practice since the time at which a maximum plasma concentration occurs is not constant until steady state is attained. 

Once the time at which maximum plasma concentration of drug occurs at steady state is known, the maximum plasma concentration at steady state can be derived by substitution of f ax in the following equation, Eq. 12.4  

Peak plasma concentration following the administration of a single extravascular dose, or the first dose, is obtained as follows  

Equation 12.13 permits determination of peak plasma concentration for a drug administered extravascularly provided the intercept value for an identical single dose, peak time, elimination half life and the dosing interval are known. 

It will be very helpful to begin to compare Eq. 11.12 (for an intravenous bolus) and Eq. 12.13 (for extravascularly administered dose) for similarity and differences, if any, and identify the commonality between the two equations. It may he quickly apparent that the information obtained following the administration of a single dose of a drug, either intravenously or 

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The maximum and iriinimum plasma concentrations at steady state [(Cp) max and (Cp) min] following administration of a drug as an intravenous bolus or by an extravascular... 

Maximum or peak 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. 

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). 

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

The clinical development stage comprises three distinct components or phases (I, II, and III), and culminates in the filing of the NDA/MAA. Each phase involves process scale-up, pharmacokinetics, drug delivery, and drug safety activities. During phase I clinical development, the compound s safety and pharmacokinetic profile is defined. The determination of maximum concentration at steady state (Cmax), area under the plasma concentration time curve (AUC), elimination half-life, volume of distribution, clearance and excretion, and potential for drug accumulation is made in addition to studies that provide estimates of efficacious doses. Dose levels typically... 

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. 

The pharmacokinetics of lidocaine in patches have been investigated in two studies. In 20 healthy volunteers, 5% lidocaine patches were applied for 18 hours/day on 3 consecutive days (69). The mean peak concentrations on days 1, 2, and 3 were 145,153, and 154 ng/ml respectively the median values of were 18.0, 16.5, and 16.5 hours and the mean trough concentrations were 83, 86, and 77 ng/ml. The patches were well tolerated local skin reactions were generally minimal and self-limiting. In 20 healthy volunteers, 4 lidocaine patches were applied every 12 or 24 hours on 3 consecutive days (67). The mean maximum-plasma lidocaine concentrations at steady state were 225 and 186 ng/ml respectively. There was no loss of sensation at the site of application. No patient had edema and most cases of erythema were very slight. No systemic adverse events were judged to be related to the patches. 

The pharmacokinetics of hypericin and pseudohypericin piasma have been studied as weii (Brockmoiier et ai. 1997). Human subjects receiving piacebo, or 900, 1800, or 3600 mg of a standardized hypericum extract (LI 160), which contained 0, 2.81, 5.62, and 11.25 mg of totai hypericin and pseudohypericin, achieved maximum total plasma concentrations at 4 hours (0.028, 0.061, and 0.159 mg/L, respectively). The half-lives of absorption, distribution, and elimination were 0.6, 6.0, and 43.1 hours, respectively, using 750 pg of hypericin, and are slightly different for 1578 pg of pseudohypericin (1.3, 1.4, and 24.8 hours, respectively) (Kerb et ai. 1996). The systemic availability of the hypericum extract LI 160 is between 14 and 21%. Comparable results are found in another study using LI 160 (Staffeldt et ai. 1994). Long-term dosing of 3 x 300 mg per day showed that steady-state levels of hypericin are reached after 4 days. 

Phase I clinical evaluation of BMS 599626 is ongoing [79,80] however, no efficacy data have been reported to date. Dose escalation has proceeded to 660 mg/day and is ongoing since a MTD has not been reached. The pharmacokinetic profile in both healthy volunteers and cancer patients supports once-daily dosing with a half-life of ca. 20 h. An area under the curve of ca. 2.4 xgh/ml with a maximum concentration of ca. 0.18 xg/ml was achieved at steady state after 100-mg dosing in patients. In mice at a dose that resulted in modest antitumor activity (ca. 50% TGI), significantly higher plasma levels were achieved (AUC ca. 14.5 xgh/ml and Cmax ca. 5.0 xg/ml) [76]. 

In humans, the mean maximum plasma concentration (Cmax) is 79 ng/mL and the time to achieve Cmax was 2.67 h after a single 3-h infusion of decitabine (1) at 15 mg/m2. At this dose, the volume of distribution at steady state is 148 mL/kg, and the total plasma clearance is 122 L/kg/m2. The terminal half-life is approximately 35 min as decitabine (1) is primarily metabolized in the liver by cytidine deaminase to yield noncytotoxic 5-aza-2 -deoxyuridine. Urinary excretion of unchanged decitabine (1) is low (0.01-0.9% of total dose).13... 

Maximum plasma concentrations of the inhibitors at steady state reported in literature. Unbound fractions of the inhibitors in human plasma. 

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.

In Eq. 11.12, the term (Cp ) or represents the maximum plasma concentration of a drug in the body at the steady-state condition (i.e. following the administration of many doses). This maximum will occur only at f=0 (immediately after administration of the latest bolus dose) since 1, when t=0). 

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... 

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. 

Assuming that the fraction of each dose absorbed is constant during a multiple-dosing regimen, the time at which a maximum plasma concentration of dmg at steady state occurs (t max) can be obtained by differentiating the following equation with respect to time and setting the resultant equal to 0. 

In a study in healthy subjects, efavirenz 400 mg daily decreased the steady-state maximum plasma levels and the AUC of voriconazole 200 mg twice daily by 61% and 77%, respectively. At the same time, the steady-state maximum plasma levels and the AUC of efavirenz were increased by 38% and 44%, respectively. In a dose-adjustment study, when voriconazole 300 mg twice daily and efavirenz 300 mg daily were used together, the AUC of voriconazole was 55% lower than that seen with the standard dose of voriconazole 200 mg twice daily alone, and the efavirenz AUC was equivalent to that seen with efavirenz 600 mg daily alone. " In a further dose-adjustment study, when voriconazole 4(X) mg twice daily was given with efavirenz 300 mg once daily, the AUC of voriconazole was just 7% lower than that seen with voriconazole 200 mg twice daily alone. The AUC of efavirenz was increased by 17% and the maximum plasma concentration was equivalent, when compared with efavirenz 600 mg once daily alone. " ... 

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