Steady-state plasma concentration minimum

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,... 

Fig. 9. Relationship between amelioration scores in depressed patients and steady-state plasma concentrations of the antidepressant nortriptyline. Both low and high concentrations are associated with minimum therapeutic effect. (From Asherg M, Cronholm B, Sjoqvist F, Tuck D. Relationship between plasma level and therapeutic effect of nortriptyline. Br Med J 1971 3 331-4, with permission from the BMJ Publishing Group.)...

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). 

Following oral administration of 20 mg twice a day to 9 subjects, minimum steady-state plasma concentrations of 0.02 to 0.20 (ig/ml (mean 0.09), and erythrocyte concentrations of 0.01 to 0.06pg/ml (mean 0.03) were reported therapeutic effect appeared to correlate with erythrocyte concentrations in the range 0.03 to 0.06 pg/ml (R. Casper et al., Archs gen. Psychiat., 1980, 57, 301-305). 

Peak plasma concentrations of 0.010 to 0.026 pg/ml (mean 0.018) were reported 3 hours after administration of a single oral dose of 150 mg to 6 subjects (L. E. Hollister eta/., Clin. Pharmac. Ther., 1970,11, 49-59). Following daily oral doses of 200 to 600 mg to 10 subjects, minimum steady-state plasma concentrations of 0.002 to 0.122 pg/ml (mean 0.03) of chlorpromazine were reported monodesmethylchlorpromazine and 7-hydroxychlorpromazine plasma concentrations averaged 16% and 30% respectively of the chlorpromazine plasma concentration, but there were considerable intersubject variations (G. Alfredsson etal. Psychopharmacology, 1976,4< , 123-131). 

Following oral administration of 200 mg five times a day to 10 subjects, minimum steady-state plasma concentrations of 0.26 to 0.80 ig/ml (mean 0.4) were reported steady-state plasma concentrations of the sulphoxide metabolite ranged from 0.07 to 0.21 pg/ml (mean 0.12) (R. Larsson, Br. J. din. Pharmac., 1982,13,163-170). 

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... 

During daily oral dosing with 30 mg/kg to 7 subjects, minimum steady-state plasma concentrations of 4.5 to 14 pg/ml (mean 10) were reported following daily oral treatment with 60 mg/kg to 6 subjects, minimum steady-state plasma concentrations of 14 to 50 pg/ml (mean 30) were reported (O. Spetal., Clin. exp. Pharmac. Physiol., 1975,2,185-192). 

Following repeated oral administration of 5 mg every 4 hours to 8 patients, a mean minimum steady-state plasma concentration of 0.011 pg/ ml was reported in 8 patients receiving 30 mg every 4 hours, a mean minimum steady-state plasma concentration of 0.044 pg/ml was reported (T. D. Walsh and B. V. Kadam, Br. J. din. Pharmac., 1984,17,232P). 

Following chronic oral doses of 100 to 400 mg daily to 14 subjects, minimum steady-state plasma-perhexiline concentrations of 0.35 to 2.8 pg/ml (mean 1.07) were reported steady-state plasma concentrations of the major monohydroxylated metabolite ranged from 1.25 to 7.4 pg/ml (mean 3.8). Steady-state plasma concentrations in 13 subjects who had been receiving similar daily doses but had developed toxic effects were ... 

Oral dosing of 5 subjects with 800 mg of sulphamethoxazole and 160 mg of trimethoprim twice daily, produced minimum steady-state plasma concentrations of about 55 pg/ml of sulphamethoxazole and 1.7 pg/ml of trimethoprim, on the ninth day (P. Kremers et al., J. clin. Pharmac., 1974, /4,112-117). 

Following a single oral dose of 2 g to 8 subjects, peak plasma concentrations of 7 to 32 pg/ml (mean 17) of sulphasalazine were attained in about 3 hours peak plasma concentrations of sulphapyridine averaged about 20 pg/ml (E. M. Ryde and J. J. Lima, Curr. ther. Res., 1981,29, 728-737). Following daily oral doses of 3 g to 6 subjects, minimum steady-state plasma concentrations of 0.04 to 0.34 pg/ml of 5-aminosalicylic acid and... 

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 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. 

Koyama et al. (1996) evaluated the steady-state plasma levels of imipramine and desipramine in 28 Japanese patients with depression after they had received fixed doses of imipramine for a minimum of 2 weeks to phenotype for CYP2C19 metabolizer status. The authors found that the mean desipramine concentration-to-imipramine concentration ratio (N-demethylation index) was significantly reduced in patients who were designated PMs, compared with those who were designated EMs. 

A designed dosage regimen allows prediction to be made of the maximum desirable and minimum effective steady-state plasma drug concentrations ... 

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.

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 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 ... 

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

It is possible to predict the steady-state minimum plasma concentration (Fig. 6.4) using the equation ... 

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. 

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. 

Relationship between frequency of dosing and maximum and minimum plasma concentrations when a steady-state theophylline... 

---