Mean plasma concentration-time curves

Figure 29.2 Mean plasma concentration-time curves following either systemic (intravenous) or local (subcutaneous) administration of VB4-845 on day 1. VB4-845 was not detected at 24 hours in either mode of drug administration.

Mean plasma concentration-time curves for total verapamil (i.e., the mixture of both enantiomers) as measured in 20 healthy volunteers receiving... 

Fig. 7 Mean plasma concentration-time curves of intact [ H]-(Asu )-eel calcitonin after intravenous (0.68 pg open triangle), intranasal liquid (1.68 pg open circle), and intranasal powder (1.54pg closed circle) administration in rats. The mean SEM (n = 3). (Reprinted from Ref. with permission from Elsevier.)...

In Equation 17.22, the body is considered as a single homogeneous pool of body fluids as described above for digoxin. For most drugs, however, two or three distinct pools of distribution space appear to exist. This condition results in a time-dependent decrease in the measurable blood or plasma concentration, which reflects distribution into other bod pools independent of the body s ability to eliminate the drug. Figure 17.3 describes mean serum IFN-a concentrations after a 40-min intravenous infusion as well as after intramuscular and subcutaneous injections of the same dose. Note the logarithmic biphasic nature of the mean plasma concentration-time curve after the intravenous infusion. This biphasic nature represents both the distribution and elimination processes. 

FIGURE 8.5 Mean plasma concentration-time curve for preclinical candidates and its three metabolites following single po dosing to rats. Line identification , parent , alcohol metabolite A, acid metabolite , aldehyde metabolite. 

FIGURE 8.7 Mean plasma concentration-time curve for clinical candidates from dose escalation PK study in rats. Line identification , dose size 1 mg/kg , dose size 30 mg/kg. 

Indinavir was rapidly absorbed in the fasted state, with a time to peak plasma concentration of 0.8 0.3 hours (mean S.D.) (n=l 1). A greater than dose-proportional increase in indinavir plasma concentrations was observed over the 200-1000 mg dose range. At a dosing regimen of 800 mg every 8 hours, the steady-state area under the plasma concentration time curve (AUC) was 30,691 11,407 nM-hour (n=16), peak plasma concentration was 12,617 4037 nM (n=16), and plasma concentration eight hours post dose (trough) was 251 178 nM... 

Sertraline pharmacokinetics were described in 61 children and adolescents (ages 6 to 17) with depression or OCD (Alderman et ah, 1998). Mean area under the plasma concentration-time curve, peak plasma concentration, and elimination half-life for sertraline and des-methylsertraline were similar to previously reported adult values. No differences between children and adolescents were apparent when values were normalized for body weight. 

Fexofenadine mean plasma concentration-time profile obtained using corresponding calibration curves on opposite column... 

Figure 1.6. Fexofenadine calibration curves and mean plasma concentration-time profiles following a single oral administration of (a) 100 pug (microdosing) or (b) 60 mg (clinical dosing) fexofenadine to healthy volunteers. (Reprinted with pemnission from Yamane et al., 2007.)...

Fig. 2.5 Nonlinear pharmacokinetics ofM-CSF, presented as measured and modeled plasma concentration-time curves (mean SE) after intravenous injection of 0.1 mg/kg (n = 5), 1.0 mg/kg (n = 3), and 10 mg/kg (n = 8) in rats (from [97]).

Figure 2 Mean ( SE) plasma concentrations of triazolam (left) or alprazolam (right) in a series of healthy individuals who participated in a clinical pharmacokinetic study. In one phase of the study, they ingested a single 0.25-mg oral dose of triazolam with ketoco-nazole, 200 mg twice daily, or with placebo to match ketoconazole (control). In the second phase of the study, they took 1.0 mg of alprazolam orally, either with the same dosage of ketoconazole or with placebo to match ketoconazole (control). Note that ketoconazole increases AUC and reduces clearance of both triazolam and alprazolam. For triazolam (a high-extraction compound), the effect is evident as reduced presystemic extraction, increased Cmax, and prolonged half-life. However, for alprazolam (a low-extraction compound), the effect of ketoconazole is evident only as a prolongation of half-life. Abbreviation AUC, the plasma concentration-time curve. Source Adapted, in part, from Ref. 74.

Cmax = peak plasma concentration rl/2c, = distribution half-life /l2 i = elimination half-life AUC = area under the plasma concentration-time curve Cl = total body clearance Fd = volume of distribution. Values shown are mean SD (n = 2). 

FIGURE 20 Individual plasma concentration-time curves for midazolam (solid lines) and 1-hydroxymidazolam (broken lines) after intranasal administration of 5 mg midazolam. The bold curves represent the mean pharmacokinetic model fit to the data. (Reproduced from ref. Ill with permission of Blackwell Publishing.)... 

In another study carried out in fasted ponies, the oral administration of a flunixin meglumine paste (l.lmg/kg) resulted in peak plasma concentrations >2 jLg/ml less than 1 h after administration (Welsh et al 1992). In ponies with free access to hay, the peak plasma concentration decreased to approximately 1.3 j,g/ml and the peak concentration was not reached until 7.6 h after administration (Welsh et al 1992). Nevertheless, the mean area under the plasma concentration-time curve (AUC) was not significantly different whether the ponies had been fasted or fed. The parenteral preparation of flunixin meglumine can be administered i.m. however, necrotizing soft-tissue infections have been reported following i.m. administration (Kahn Styrt 1997) and so aseptic preparation of the injection site is advisable. 

PHARMACOKINETICS The area under the plasma concentration-time curve (AUC) was identified, in a preliminary analysis, as the important exposure covariate that was predictive of the safety biomarker outcome. Consequently, it became necessary to compare the distributions of AUC values across studies and dosage regimens. Figure 47.8 illustrates distributions of the exposure parameter AUC across studies. It is evident that AUC values are higher in diseased subjects than in healthy volunteer subjects at the same dose level. To adjust for the difference between the two subpopulations, an indicator function was introduced in a first-order regression model to better characterize the dose-exposure data. Let y be the response variable (i.e., AUC), X is a predictor variable, P is the regression coefficient on x, and e is the error term, which is normally distributed with a mean of zero and variance cP. Thus,... 

Few drugs are given Intravenously. This means that for most drugs the fraction which is absorbed intact into the circulation is often very much less than unity. This fraction, F, is referred to as the bioavailability. The bioavailability of oral formulations is often established in special studies (usually cross-over studies in healthy volunteers) in which the area under the plasma - concentration time curve (AUC) of the oral formulation is compared with that of an intravenous formulation. The bioavailability can then be calculated as the ratio of AUC to dose delivered for the oral formulation to the corresponding ratio for the intravenous formulation. Since the total amount eliminated from the body is equal to the clearance times the AUC, and since the total amount eliminated equals the amount absorbed, which is simply the dose times the bioavailability, so dose, AUC, bioavailability and clearance are linked by the formula, F x Dose = Clearance x AUC. For many drugs the bioavailability and clearance are independent of the dose administered. This property is referred to as dose-proportionality and is... 

Vs = dose AUMC/(AUC) where AUMC is area under first moment of plasma concentration-time curve Vs = CVMRT, with MRT the mean residence time Krea = Cl/tcrminal slope... 

In another study the area under the plasma concentration-time curve for prednisolone for the 20 mg dose was 77.89 % of that calculated for the 10 mg dose. This change in area represented an increase in prednisolone clearance from 1,7 ml/min kg to 2.2 ml/min kg when the dose was increased (141). Rose et al. (142) found dose-dependent pharmacokinetics of prednisolone where the plasma half-life increased from 3 to 5 h as the oral dose of prednisone was increased from 5 to 50 mg. Tanner et al (143) reported the pharmacokinetics of prednisolone at different dose levels in 43 subjects. Each subject received only a single dose, 5 - 200 mg of oral prednisolone. Kinetic parameters of oral prednisolone are presented in table 5 and fig. 13 illustrates concentration-time profile of prednisolone. The mean half-life of prednisolone remained fairly constant between 3.4 to 3.8 h. Bioavailability of prednisolone was 98.5 i 4 %. Furthermore as the prednisolone dose increased, the area under the curve increased but not proportionally to the dose, such that a fivefold increase in dose from 20 to 100 mg resulted in only a two-to threefold increase in area under the curve. 

Figure 4 Mean SEM plasma concentration-time curves of total verapamil (left panel) and enantiomeric (R/S) ratios (right panel) in 12 healthy young men who each received a 240 mg single dose of racemic verapamil as immediate-release (IR fasting) and sustained-release (SR fed) formulations in a randomized crossover study. Insets show mean SEM for the individual peak concentration (Cniax) (total) and R/S ratios associated with these Cmax (total) values. p<0.05. (From Ref. 26, with permission.)...

Figure 7 Ibuprofen, a prototype category II racemic drug with chiral inversion. Mean (w = 4) plasma concentration-time curves of R-ibuprofen, S-ibuprofen, and enantiomeric S/R ratios after oral administration of racemic ibuprofen given as an immediate-release (upper panel three 200 mg doses 6 hours apart) and controlled-release formulation (lower panel two 300 mg doses 12 hours apart). The arrows on the time axes indicate the time of drug administration. (From Ref. 26, with permission.)... 

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). 

Figure 7.26(a) Representative plasma concentrations of griseofulvin following oral administration of 50 mg/kg of griseofulvin suspended in lipid vehicles and water. Each curve, representing data from one animal, has a peak plasma concentration and fmax closest to the mean values for each group. For key, see Fig. 7.25. Inset correlation of the area under the plasma concentration-time curve (AUC) with the average 0 to 4 h rate of release of griseofulvin in vitro, (b) Release of griseofulvin into water from suspensions containing 5 mg drug in lipid and water. Each point represents the mean of three experiments. Key as above. From Bloedow and Hay ton [79] with permission.

Sohn et al. [148] examined the kinetic variables of omeprazole and its two primary metabolites in plasma, 5-hydroxyomeprazole and omeprazole sulfone, and the excretion profile of its principal metabolite in urine, 5-hydroxyomeprazole, in eight extensive metabolizers and eight poor metabolizers. Each subject received a postoral dose of 20 mg of omeprazole as an enteric-coated formulation, and blood and urine samples were collected up to 24 h postdose. Omeprazole and its metabolites were measured by HPLC with UV detection. The mean omeprazole area under the concentration-time curve, elimination half-life, and apparent postoral clearance were significantly greater, longer, and lower, respectively, in the poor metabolizers than in the extensive metabolizers. The mean cumulative urinary excretion of 5-hydroxyomeprazole up to 24 h postdose was significantly less in the poor metabolizers than in the extensive metabolizers. 

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