Peak plasma concentration determination

Pharmacokinetic concentration-time curves for a drug and ifs mefabolifes are used to identify primary exposure metrics such as AUC, or which are not time-dependent unlike the sequential measurements of concentration over time. A peak plasma concentration of a drug is often associated with a PD response, especially with an adverse event. There can be large inter-individual variability in the time-to-peak concentration, and closely spaced sampling times are often critical to determining the peak plasma concentration accurately in individual patients because of differences in demographics, disease states, and food effects, if any. All these elements are clearly spelled out in the protocols written to conduct these studies. 

Absorption - Atier ora administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10 mg dose of ezetimibe to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax)- The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection. Ezetimibe has variable bioavailability the coefficient of variation, based on intersubject variability, was 35% to 60% for area under the curve (AUC) values. 

Aminoglycosides are most useful for bacteraemias (especially Gram-negative septicaemia) since their volume of distribution is relatively low. With the exception of patients with renal failure or endocarditis they should be administered once-daily. This is because they exhibit a dose-dependent pharmacodynamic effect. This means that bactericidal activity is determined more by the peak plasma concentration than by the time that the plasma concentration is above the minimum required to achieve bacterial killing. The converse is true of p-lactams, which exhibit t/me-cfepenofent bacterial killing. 

Metabolism often plays a central role in the efficacy of a drug and/or the toxicity associated with exposure to a drug or other xenobiotics. Metabolism may convert a prodrug to the pharmacologically active form, and may be a primary determinant of peak plasma concentration and half-life. Alternatively, competition for metabolism may be the mechanism for a drug-drug interaction. 

Pharmacokinetic studies with sheep treated with the recommended dosage showed that praziquantel was rapidly absorbed, peak plasma concentration being reached within 2 h of dosing (72). A half-life of 4.2 h was determined and excretion from plasma was rapid, 98% being excreted within 72 h. At 8 h posttreatment, the maximum levels present in liver, kidneys, muscle, and fat were 2.87, 2.55, 0.19, and 0.1,3 ppb, respectively, of praziquantel equivalents. At 24 h post-... 

Various factors may account for the variability in response to neuroleptics. These include differences in the diagnostic criteria, concurrent administration of drugs which may affect the absorption and metabolism of the neuroleptics (e.g. tricyclic antidepressants), different times of blood sampling, and variations due to the different type of assay method used. In some cases, the failure to obtain consistent relationships between the plasma neuroleptic concentration and the clinical response may be explained by the contribution of active metabolites to the therapeutic effects. Thus chlorpromazine, thioridazine, levomepromazine (methotrime-prazine) and loxapine have active metabolites which reach peak plasma concentrations within the same range as those of the parent compounds. As these metabolites often have pharmacodynamic and pharmacokinetic activities which differ from those of the parent compound, it is essential to determine the plasma concentrations of both the parent compound and its metabolites in order to establish whether or not a relationship exists between the plasma concentration and the therapeutic outcome. 

Insulin cannot be taken as a pill as it is broken down during digestion, similar to protein in food. Therefore it is injected under the skin (subcutaneously). There are more than 20 different preparations of insulin available, but essentially there are four classes determined by the speed of onset, the time of reaching the peak plasma concentration and the duration of activity in the body ... 

Following oral administration of 400 mg to 7 subjects, peak plasma concentrations of about 0.5 to 1 pg/ml were attained in about 7 hours. After administration of 200 mg 8-hourly to 6 subjects for one month, plasma concentrations determined immediately before the morning dose ranged from 0.75 to 2.8 pg/ml (mean 1.5) (F. Andreasen et al., Eur. J. din. Pharmac., 1981,19, 293-299). 

Following a single oral dose of 1 g given to 12 slow acetylators and 11 rapid acetylators (determined with reference to dapsone), the following mean peak plasma concentrations ( ig/ml, time in hours) were reported ... 

After a single oral dose of 40 mg to 13 subjects, peak plasma concentrations of the desacetyl metabolite of 0.034 to 0.214 pg/ml (mean 0.14) were attained in about 1 hour. Oral administration of 20 mg twice daily to 6 subjects, produced mean steady-state plasma concentrations (desacetyl derivative) of 0.06 to 0.08pg/ml determined on the 6th to 8th day considerable intersubject variation was reported (O. Mayer, Int. J. din. Pharmac. Ther. Toxicol., 1980,18, 113-120). 

Meclofenamic acid is an anthranilic acid derivative that is typically administered orally to horses. The pharmacokinetics of this NSAID in horses has been well defined. For example, the plasma half-life in horses has been determined in several studies and varies between 0.7 and 1.4 h (Johansson et al 1991, Snow et al 1981). Absorption is variable after oral dosing with estimates of bioavailability ranging from 60 to 90% and peak plasma concentrations occurring 1-3 h after administration (Johansson et al 1991). The effect of ingesta on the absorption of meclofenamic acid from the gastrointestinal tract has not been determined definitively. In one study, the absorption rate of the NSAID was the same in ponies whether they were fasted or fed (Snow et al 1981). However, another study found that absorption of meclofenamic acid was delayed in horses allowed free access to hay (May Lees 1999). In horses, the liver metabolizes meclofenamic acid primarily by oxidation to an active hydroxymethyl metabolite, which may be further oxidized to an inactive carboxyl metabolite (Plumb 1999). 

The variety of methods that may be used to estimate the rate of drug absorption shows the uncertainty associated with determining this component of bioavailability. Fortunately, the extent of absorption (systemic availability), in conjunction with the peak plasma concentration and apparent half-life, is of greater interest in designing drug dosage regimens. 

Bupropion oral bioavailability in humans has not been determined becausethe drug was never administered intravenously to humans. The relative oral bioavailability in rats and dogs ranges between 5%and 20%. In healthy volunteers, peak plasma concentration is reached approximately 3 h after administration of the sustained release tablet (93). Based on in vitro protein binding data, bupropion is 84%bound to plasma proteins. It is widely distributed to tissues and has an apparent steady-state volume of distribution (V JF) of approximately 2000 L. Bupropion is extensively metabolized by oxidation and reduction to at least six metabolites with only 0.5% of a bupropion oral dose excreted unchanged in urine. The major metabolite in urine is a glycine conjugate of metachlorobenzoic acid. 

In a more recent study in which the level of intact drug was carefully evaluated using capillary gel electrophoresis, the pharmacokinetics of ISIS 2302, a 20-mer phosphorothioate oligodeoxynucleotide, after a 2-h infusion, were determined. Doses from 0.06 to 2.0 mgkg were studied and the peak plasma concentrations were shown to increase linearly with dose, with the 2 mg/kg dose resulting in peak plasma concentrations of intact drug of about 9.5 Ltg/mL. Clearance from plasma, however, was dose dependent, with the 2 mg/kg dose having a clearance of 1.28 mL min kg-, whereas that of 0.5 mg/kg was... 

Solubility Is another factor determining the rate of dissolution. As solubility increases, so does the dissolution rate. One way of increasing solubility is to use salts. Salts of weak acids and weak bases generally have much higher aqueous solubility than the free acid or base therefore, if the drug can be given as a salt, the solubility can be increased, and we should have improved dissolution (Fig. 9.18). This factor can lead to quite different peak plasma concentrations after oral administration. 

The useful estimate of relative absorption rates of a drug from different products, through different routes of administration or different conditions (i.e., with or without food or in the presence of other drugs, etc.) can be made by comparing the magnitude of time of occurrence of peak concentration, peak concentration, and area under the peak plasma concentration curve, (AUC)"q. The peak time and peak plasma concentration can be determined by employing Equations 9.74 and 9.76 or 9.79, respectively, and the extent of absorption can be determined as described below. 

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