Steady-state plasma concentration maximum

In this special case when the time between dosings is equal to the half-life time of the drug, we can deduce that the minimum (steady-state) plasma concentration with repeated dosing is equal to the peak concentration, obtained from a single dose. Under this condition, the corresponding maximum (steady-state) concentration is twice as much as the minimum one. 

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,... 

Human clinical studies Plasma levels of hyperforin were followed for 24 hours in two studies with healthy volunteers after administration of film-coated tablets containing 300 mg SJW extract representing 14.8 mg hyperforin (Table 2) (72). In the first crossover study, six male volunteers received 300, 600, or 1200 mg of a SJW extract preparation (WS 5572, Dr. Willmar Schwabe Arzneimittel, Karlsruhe, Germany) after a 10-hour fasting time. Maximum plasma levels of 150 ng/mL (approximately 280 nM) were reached after 3.5 hours after intake of 300 mg SJW extract. Half-life and MRT were 9 and 12 hours, respectively. Hyperforin pharmacokinetics were linear up to 600 mg of the extract. Increasing the doses to 900 or 1200 mg resulted in lower Cmax and AUC values than those expected from linear extrapolation of data from lower doses. In a repeated dose study with seven healthy volunteers, no accumulation of hyperforin in plasma was observed after intake of 900mg/day SJW extract for seven days. The estimated steady-state plasma concentrations of hyperforin after intake of 3 x 300mg/day was approximately 100 ng/mL (approximately 180 nM) (Table 2) (72). 

Relationship between frequency of dosing and maximum and minimum plasma concentrations when a steady-state theophylline plasma level of 10 mg/L is desired. The smoothly rising line (solid black) shows the plasma concentration achieved with an intravenous infusion of 28 mg/h. The doses for 8-hourly administration (light color) are 224 mg for 24-hourly administration (dark color), 672 mg. In each of the 3 cases, the mean steady-state plasma concentration is 10 mg/L. 

After a single oral dose of 1 mg given to 10 subjects, peak plasma concentrations of 0.011 to 0.020 pg/ml (mean 0.015) were attained in about 1.75 hours. Following daily oral doses of 0.5 mg three times a day to the same subjects, minimum steady-state plasma concentrations of 0.006 to 0.017 pg/ml (mean 0.011) and a mean maximum steady-state plasma concentration of 0.018 pg/ml were reported (R. B. Smith et al., Clin. Pharm., 1983,2,139-143). 

After a single oral dose of 100 mg given to 12 subjects, peak plasma concentrations of 0.41 to 0.87 pg/ml (mean 0.6) were attained in about 3 hours (J. McAinsh et al., Biopharm. Drug Disp., 1980, 7, 323-332), Following daily oral doses of 25, 50 and 100 mg to 7, 7, and 6 subjects respectively, mean maximum steady-state plasma concentrations of 0.12, 0.22, and 0.39 ig/ml were reported 4 hours after a dose the corresponding mean trough concentrations were 0.02, 0.04, and 0.07 ig/ml (T. Ishizaki etaL, Br. J. din. Pharmac., 1983,16, 17-25). 

After a single oral dose of 100 mg given to 6 subjects, peak serum concentrations of about 2 xg/ml were attained in 1 hour (F. Nielsen-Kudsk and A. K. Pederson, Acta pharmac. tox., 1979,44, 391-399). Following oral administration of 50 mg three times a day to 10 subjects, maximum steady-state plasma concentrations of 0.4 to 2.6 pg/ml (mean 1.4) were reported trough concentrations were 0.1 to 1.5 ig/ml (mean 0.7). In 10 subjects given 75 mg twice daily, the corresponding maximum and minimum steady-state concentrations were 0.5 to 4 pg/ml (mean 1.7) and 0.1 to 2.6 pg/ml (mean 0.9) (C. Mahony et al., J. din. Pharmac., 1983, 23,123-126). 

Following oral administration of 250 mg of erythromycin four times a day to 16 subjects, maximum and minimum steady-state plasma concentrations of 1.7 and 0.45 pg/ml were reported on the third day, compared to 1.34 and 0.58 pg/ml respectively, following repeated oral administration of erythromycin estolate (A. R. DiSanto et al., J. din. Pharmac., 1980, 20, 437-443X... 

Following daily oral doses of 10 to 25 mg/kg to 18 children for 3 weeks, maximum steady-state plasma concentrations of 52 to 372 ig/ml (mean 120) were reported 2 to 8 hours after a dose (A.-L. Makela et al., Eur. J. din. Pharmac., 1983, 25, 381-388). 

After daily oral doses of 300 mg to 8 subjects, a mean maximum steady-state plasma concentration of 3.7 pg/ml was reported (R. K. Nayak et ai, J. Pharmacokinet. Biopharm., 1974,2, 107-121). 

Following weekly oral administration of 30, 60 and 120 mg for 13 weeks to 7, 7 and 8 subjects, mean steady-state plasma concentrations of about 0.004 to 0.01, 0.006 to 0.012, and 0.008 to 0.025 fig/ml were reported. In all subjects maximum concentrations were attained within 12 hours of a dose concentrations declined rapidly between 12 and 24 hours followed by a much slower decline during the next 120 hours and were still significant (about 0.001 pg/ml) 168 hours after the dose (S. F. Cooper et aL, Clin. Pharmac. Ther., 1975,18, 325-329). 

Following oral administration of 40 mg to 20 subjects, peak plasma concentrations of 1.7 to 6.8 pg/ml (mean 4.3) were reported multiple peak concentrations were observed in 16 subjects, suggesting possible enterohepatic circulation. After daily oral administration of 10, 20, and 30 mg to 5 subjects for 14 days, maximum steady-state plasma concentrations of 2.1 to 4.3 (mean 3.2), 3.6 to 6.5 (mean 4.5), and 9.0 to 16.5 (mean 11.7) pg/ml were reported (D, C. Hobbs and T. M. Twomey, J. din. Pharmac., 1979,19, 270-281). 

Following oral administration of 60 mg 4 times a day to 17 subjects, maximum steady-state plasma concentrations of 0.41 to 0.79 pg/ml (mean 0.55) were reported about 1.5 hours after a dose (J. G. Perkins et aL, Curr. ther. Res., 1980, 28, 650-668). 

Following daily oral doses of 60 to 660 mg to 6 subjects, maximum steady-state plasma concentrations of 0.04 to 0.08 pg/ml were reported (T. N. Calvey and K. Chan, Clin. Pharmac. Ther., 1977, 21, 187-193). 

Maximum steady-state plasma concentrations of 51 to 69)ig/ml (mean 58) were reported on the seventh day after 6 subjects had received an initial dose of 600 mg followed by 200 mg daily (D. S. Reeves et al., J. antimicrob. Chemother., 1980, 6, 647-656). 

Following daily oral doses of 200 mg, twice a day to 12 subjects, mean maximum steady-state plasma concentrations were sulindac S.Opg/ml, sulphide 6.9 ig/ml, sulphone 2.6pg/ml a diurnal variation in plasma concentrations was reported with lower concentrations being attained after the evening dose. After oral administration of 400 mg once daily to 12 subjects, maximum steady-state plasma concentrations were sulindac 8.7 ig/ml, sulphide 8.8 pg/ml, sulphone 3.9 ig/ml (B. N. Swanson et al., Clin. Pharmac. Ther., 1982, 32, 397-403). 

Following oral administration of 400 mg twice a day to 10 subjects (in combination with trimethoprim 80 mg), a mean maximum steady-state plasma concentration of 75 pg/ml and a mean trough concentration of 42 pg/ml were reported (I. D. Watson et al., Br. J. din. Pharmac., 1982, 14, 437-443). 

Following oral administration of400 mg four times a day to 5 subjects for 7 days, maximum steady-state plasma concentrations of 8.3 to 78.9 pg/ml (mean 45) of tolmetin and 4.1 to 13.6 pg/ml (mean 10) of the dicarboxylated metabolite were reported about 0.75 and 1.75 hour after a dose, respectively (S. H. Dromgooleet a/., Clin. Pharmac. Ther., 1982, 32, 371-2,11). 

Following chronic oral doses of 80 mg 6-hourly to 16 subjects, steady-state trough plasma concentrations of 0.031 to 0.168 pg/ml (mean 0.105) of verapamil, and 0.078 to 0.279 pg/ml (mean 0.171) of norverapamil were reported maximum steady-state plasma concentrations were 0.135 to 0.447 pg/ml (mean 0.255) and 0.134 to 0.361 pg/ml (mean 0.226) for verapamil and norverapamil respectively, attained 1 hour after a dose (S. B. Freedman era/., Clin. Pharmac. Ther., 1981,30,644-652). 

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. 

Letrozole is rapidly absorbed after oral administration and maximum plasma levels are reached about 1 hour after ingestion. Letrozole has a bioavailability of 99.9%. Steady-state plasma concentrations of letrozole are reached after 2 to 6 weeks of treatment. Following metabolism by CYP2A6 and CYP3A4, letrozole is eliminated as an inactive carbinol metabolite mainly via the kidneys. Due to the low total body clearance (2.21 L/h), the elimination half-life is about 40 to 42 hours. 

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 ... 

Table 11.2 shows that more frequent dosing (i.e. smaller N value) results in smaller ratio of maximum to minimum steady-state plasma concentrations. 

No clinically important pharmacokinetic interactions have been found to occur between aspirin 975 mg and misoprostol 200 micrograms, or between ibuprofen and misoprostol. One study found that misoprostol 800 micrograms daily decreased the AUC of a single 100-mg dose of diclofenac by a modest 20%. However, other studies have found that misoprostol had no effect on steady-state diclofenac pharmacokinetics. One study found that misoprostol 200 micrograms raised the steady-state levels of indometacin 50 mg three times daily by about 30%, whereas another found that misoprostol 400 micrograms twice daily reduced the AUC of indometacin 50 mg twice daily by 13% after one dose and reduced the maximum steady-state plasma concentration by 24%. These modest changes in serum indometacin levels are unlikely to be clinically important. 

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