Pharmacokinetic parameters maximum plasma concentration

Figure 16 Changes to pharmacokinetic parameters over 13-week dosing regimen. (A) Maximum plasma concentration (Cmax) of DFP determined after single doses of 10, 30, or 100 mg/kg of DFP compared to the Cmax after 13 weeks of dosing. (B) AUC after a single dose of 10, 30, or 100 mg/kg of DFP compared with the Cmax after 13 weeks of dosing. Abbreviations DFP, [(5,5-dimethyl-3-(2-propoxy)-4-(4-methanesulfonylphenyl)-2(5//)-furanone)J AUC, area under the plasma concentrationtime curve. Source From Ref. 64.

The average drug input fluxes during the 20 min dosing periods between hours 24 and 25 were calculated to be 81, 108, and 138pg/h/cm for currents of 150, 200, and 250 pA, respectively. These values, the mean maximum plasma concentration values, and the total AUC values (over the same time period) for the three IDDS treatments all increased proportionally with current. These results agree with theoretical expectations expressed by [Eq. (1)]. In addition, the variabilities in the fentanyl pharmacokinetic parameters were similar for the IDDS and IV treatments, indicating that the IDDS doses were delivered with an accuracy similar to the IV infusions. 

The major pharmacokinetic parameters of albuterol and terbutaline are listed in Tables 1 and 2. Irrespective of the route of administration, the pharmacokinetics of racemic albuterol are stereoselective with a faster disappearance of the active R enantiomer from plasma (Tables 1 and 2). This is due to stereoselective metabolism and renal clearance of albuterol in favor of the R enantiomer. Both the total body and renal clearances of R-albuterol are approximately 2 to 3 times higher than those of the distomer, resulting in a >3-fold higher maximum plasma concentrations of... 

A study in patients with advanced solid tumours found that the use of capecitabine with docetaxel, resulted in an almost twofold decrease in the maximum plasma concentration and AUC of fluorouracil. The authors suggest that more study is needed to assess the significance of this finding. Other pharmacokinetic parameters of capecitabine were not affected by docetaxel, and the pharmacokinetics of docetaxel were not significantly affected by capecitabine or its metabolites. ... 

Pharmacokinetic studies in drug discovery research deal with the measurement of the drug eoneentration in plasma with respeet to time and the key parameters involved are volume of distribution (Fd), bioavailability (F), exposure (measured as the area under the curve or AUC), maximum plasma concentration attained (Cmax), time of maximum drug concentration (T ax). clearance (Cl) and half-life ( 1/2). These parameters and their role in drug discovery have been diseussed in detail in most text books related to drug metabolism and pharmaeokineties (DMPK), and have been discussed only briefly here. Eaeh of the above are defined as follows ... 

In a detailed clinical study, it was demonstrated that both enantiomers of fexofenadine possess equal potency but differ in selected pharmacokinetic parameters [10]. A 63 37 steady-state ratio of f -(-f)-l and 5-(—)-l was observed in plasma and this remained constant across time and dosing. In a later study, it was found that the AUC and the maximum plasma concentration (Cmax) of f -(-f)-l were significantly greater than those of the 5-(—)-enantiomer [11]. Furthermore, plasma and renal clearance of oral 5-(—)-fexofenadine were both significantly greater than for the f -(-i-)-enantiomer. 

An important pharmacokinetic parameter is the time of appearance of the maximum t of the plasma concentration. This can be derived by setting the first derivative of the plasma concentration function in eq. (39.16) equal to zero and solving for t, which yields ... 

The pharmacokinetic information that can be obtained from the first study in man is dependent on the route of administration. When a drug is given intravenously, its bioavailabihty is 100%, and clearance and volume of distribution can be obtained in addition to half-life. Over a range of doses it can be established whether the area under the plasma concentration-time curve (AUC) increases in proportion to the dose and hence whether the kinetic parameters are independent of dose (see Figure 4.1). When a drug is administered orally, the half-life can still be determined, but only the apparent volume of distribution and clearance can be calculated because bioavailability is unknown. However, if the maximum concentration (Cmax) and AUC increase proportionately with dose, and the half-life is constant, it can usually be assumed that clearance is independent of dose. If, on the other hand, the AUC does not increase in proportion to the dose, this could be the result of a change in bioavailability, clearance or both. 

A placebo-controlled, randomized clinical trial with monitoring of hypericin and pseudohypericin plasma concentrations was performed to evaluate the increase in dermal photosensitivity in humans after application of high doses of SJW extract (Table 2) (73). The study was divided into a single-dose and a multiple-dose part. In the single dose crossover study, each of the 13 volunteers received either placebo or 900, 1800, or 3600 mg of the SJW extract LI 160. Maximum total hypericin plasma concentrations were observed about four hours after dosage and were 0, 28, 61, and 159ng/mL, respectively. Pharmacokinetic parameters had a dose relationship that appeared to follow linear kinetics (73). 

Usually, the pharmacokinetic parameters are calculated from plasma rather than from whole blood data. The use of plasma-related parameters to measure organ extraction ratios and intrinsic clearance could, however, be misleading. When drug binding is similar in plasma and red blood cells, Cb Cp because /b /p. However, if the binding in plasma is greater than that in red blood cells, Cb < Cp and AUCb < AUCp and use of plasma clearance will provide an underestimate of the blood clearance. Maximum errors are of the order of 40%. If the B/P ratio is >1, the clearance determined from plasma concentrations would significantly overestimate blood clearance and could exceed hepatic blood flow. 

The brain and plasma levels and pharmacokinetics parameters after oral administration were compared for compounds 14a (MGC0039) and 14e-14h (see Table 3.4) [25], Again, 14a exhibited the best BBB penetration among the compounds evaluated. The mean maximum cerebral level of 14a was 13.22ng/g at 6h. After peaking, the cerebral concentrations decreased with an estimated half-life of 10.9 h. The cerebrum/plasma ratios of 14a at 1, 3, 6, and 24h were 0.01, 0.02, 0.03, and 1.99, respectively. The rate of elimination from the cerebrum was slower than that from the plasma. 

The objectives of a toxicokinetic program in toxicology studies are outlined in Table 3.5. These objectives may be met by characterizing one or more pharmacokinetic parameters from measurements made at appropriate time points in a toxicology study. The measurements are typically concentrations of the parent drug or metabolite in plasma or serum. However, in some cases it may be more appropriate to sample some other matrix or to quantify tissue levels. The pharmacokinetic parameters are usually area under the concentration-time curve (AUC), and maximum concentration (C ), or the duration that the concentration is above a given threshold (Q. The choice of the pharmacokinetic parameters should be made on a case-by-case basis. 

The muraglitazar pharmacokinetic parameters for the unchanged drug and radioactivity are presented in Table 18.5. The animal and human plasma concentration time profiles for radioactivity and muraglitazar are presented in Fig. 18.1. Following oral administration, the radioactivity and muraglitazar concentrations reached a maximum at 0.5-1 h in rats, dogs, monkeys, and humans. 

For data presentation, tissue radioactivity levels are expressed as nanogram-equivalents per gram tissue (Table 18.Al), and tissue/plasma ratios. The maximum concentration (Cmax) and the time to reach maximum concentration (Fmax) are obtained by visual inspection of the raw data. Pharmacokinetic parameters, included half-life (fi/2), area under the concentration-time curve... 

In a double-blind, placebo-controlled study, 12 healthy subjects were given a single 600-mg dose of ritonavir with either loperamide 16 mg or placebo. The loperamide AUC and maximum plasma level were increased threefold and 17%, respectively, by ritonavir, but no additional CNS adverse effects were seen. Anotiier study in 20 healthy subjects looked at the pharmacokinetics and pharmacodynamics of a single 16-mg dose of loperamide taken with either tipranavir 750 mg twice daily, ritonavir 200 mg twice daily or both drugs together. (Note that this dose of tipranavir is higher than tiie usual ritonavir-boosted dose of 500 mg twice daily.) Tipranavir alone reduced the maximum concentration and AUC of loperamide by 58% and 63%, respectively, whereas ritonavir increased these parameters by 83% and 121%, respectively. The combination of tipranavir/ritonavir, as is usual clinical practice, resulted in a net reduction in the maximum concentration and AUC of loperamide by 61% and 51%, respectively, similar to the effect seen with tipranavir alone. The maximum concentration and AUC of the metabolites of loperamide were also reduced. There were no clinically significant loperamide adverse effects on respiration or pupil contractility with either ritonavir alone, tipranavir alone, or the combination. ... 

Approximately one hundred studies have been published to date on the bioavailability and pharmacokinetics of individual polyphenols following a single dose of pure compound, plant extract or whole food/beverage to healthy volunteers. We recently reviewed the pharmacokinetic data available for each class to estimate average pharmacokinetic parameters including the maximum concentration in plasma (Qnax)> Tmax> the area under the plasma concentration versus time curve (Al/Q, ehmination half-life (Ti/2) and percent of dose excreted in urine (Manach and Donovan 2004). Here, we present a summary of that data... 

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