Plasma concentration over time

II.a.3. Repeated Oral Dosing with Measurements of Blood Plasma Concentration over Time... 

Slow release is aimed at sustained plasma concentrations over time. The alternative of frequent administrations leads to concentration spikes or requires constant concentration maintenance, through continuous administration. The development of slow release and controlled release systems incorporating Q[n] has so far been focused primarily on the development of methods to active ingredient release and not necessarily specific to adnfinistrafive application. 

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. 

The area under the plasma-concentration time curve, the AUC, is a useful parameter in defining fhe overall body exposure to a drug this parameter integrates the concentration-over-time fimction ... 

In a retrospective analysis of the effects of fluconazole 400 mg/day in 154 critically ill surgical patients the median plasma cortisol concentration was 158 jj.g/1 in 79 patients randomized to fluconazole and 167 pg/1 in 75 patients randomized to placebo (411). Patients randomized to fluconazole did not have significantly increased odds of adrenal dysfunction compared with patients randomized to placebo (OR = 0.98 95%CI = 0.48, 2.01). Randomization to fluconazole was not associated with a significant difference in cortisol concentrations over time. Mortality was not different between patients with and without adrenal dysfunction, nor between patients with adrenal dysfunction who were randomized to fluconazole and those randomized to placebo. 

PL2 - slope of placebo effect as a function of time (in days), Di - slope of drug effect as a function of AUC (24 h steady state), D2 - slope of drug effect as a fraction of the slope of placebo effect on time, E50 -drug effect that results in a 50% reduction in TSS, AUC - area under the plasma concentration versus time curve over 24 h at steady state calculated from individual predicted CL in the analysis. 

Pharmacokinetics is the study of the relationships between the drug dosage regimen and the changes in drug concentration over time. Typically, concentrations are measured in blood, serum or plasma, and the concentration-time profile is described by a series of equations. 

Here V s represents the volume in which a drug would appear to be distributed during steady state, AUC is the area under the plasma eoneentration time eurve, and AUMC is the area under the first moment of the plasma eoneentration time eurve, that is, the area under the eurve of the produet of time, t, and plasma concentration, over the time span zero to infinity. The volume of distribution at steady state can also be determined by compartmental methods, that is, by using the coefficients and exponents of a multiexponential fit to the data. ... 

All treatments delivered fentanyl for the first 20 min of every hour for 24 h. The three IDDS treatments employed currents of 150, 200, and 250 pA, while the IV treatment infused 50 pg of fentanyl. Blood samples were collected, and serum fentanyl concentrations were measured using a specific radioimmunoassay. Plasma data collected during and immediately following the 1st, 13th, and 25th treatments are shown in Fig. 4. The gradual upward shifts in concentration over time indicate a baseline increase due to incomplete fentanyl clearance between the hourly doses. For all treatment types, serum fentanyl concentrations rapidly increased within a few minutes after the start of each dose. 

Fulminant hepatic failure occurs in 1-5% of cases of paracetamol overdosage 3-6 days after ingestion (71), with frequent deaths in people who take 20-25 g. There is only a narrow margin between the normal maximum 24-hour dosage and that which can cause liver damage and acute hepatic failure. Undoubtedly, some people are more susceptible than most to paracetamol toxicity, since although 6 g has been reported as toxic in some cases, most toxicity is seen with 12 g upwards (72,73). Nomograms have been developed to show the relation between plasma paracetamol concentrations over time and the risk of a serious outcome (SEDA-18, 94). 

AUMC area trnder the first moment of the plasma concentration - time curve, i.e. the area trnder the curve of the product of time and plasma concentration over the time-span zero to infinity... 

ATI plasma concentration versus time profiles after i.v. administration of 1,15, and lOOmg/kg are shown in Figure 6.5-10, whereas Figure 6.5-11 shows ATF plasma concentration versus time profiles after i.v. bolus administration of 1,15, and 60 mg/ kg to rats. Noncompartmental analyses of the parameters for ATI and ATF are summarized in Table 6.5-2A and in Table 6.5-2B, respectively. ATI systemic clearance and terminal half-life seem to be dose independent, as no statistical differences were found over the dose range of 1 to lOOmg/kg p > 0.05). No differences... 

When plasma concentration, unbound concentration, the amount of drug and metabolite excreted and so forth all increase in proportion to dose, then the superposition principle applies. This means that concentration over time of a multidose treatment schedule can be calculated as the sum of the concentrations which would be observed from the individual doses were they given alone. For such drugs, the pharmacokinetics are said to be dose-independent or linear. Drugs which do not exhibit dose-proportionality can be difficult to manage. (A notorious example is alcohol.)... 

Schaad - Lanyi et al. (1987) studied the pharmacokinetics of single oral doses of clofazimine over 11 days following administration. They examined the effect of food on the bioavailability. Following administration with food the area under the plasma concentration versus time curve (AUC) and the peak plasma concentration Cmax were 62 and 30% higher respectively compared to results obtained in the fasted state. The... 

In Fig. 10.11, the plasma concentration versus time profile shows a trough. This might be attributed to an elapse in time between the completion of an intravenous bolus loading dose and the commencement of the infusion rate. The magnitude of the nadir observed in the plasma concentration versus time profile will be influenced by the elapsed time and the elimination half life of the drug. However, there is no bolus/infusion combination for a two-compartment drug that will produce a total plasma drug concentration that is constant over time the profile will have peaks and/or nadirs. This, therefore, could be an alternative explanation for the deviation from a horizontal line in Fig. 10.11. 

Rate of metabolism, or more generally elimination, is the decrease of plasma drug concentration over time. Therefore, Eq. 15.1 can be rewritten as ... 

The curve of therapeutic effect as a function of time may be temporally displaced with respect to the curve of plasma drug concentration over time, requiring the use of indirect pharmaco-kinetic/pharmacodynamic modeling. Other complicating factors may he at play. For example, over time the formation of antibodies to a protein may neutralize the protein or change its pharmacokinetic profile. At times, the blood concentration-effect relationship is so inaccessible for a particular therapeutic... 

A coefficient in the equation for plasma drug concentration over time for a two-compartment intravenous bolus model AUC area under the plasma drug concentration versus time curve... 

A situation with a similar degree of relative risk exists when the information displayed by the system is misleading but in a way that is obvions. For example, snppose a trend line showing changes in plasma haemoglobin concentration over time on one occasion dips down to a value of zero (Day 21 in Fig. 14.1) whilst all other instances of the assay appear appropriate and correct. 

In the in vivo human skin model, a hand is generally placed in the solution under study or a predetermined skin area from the back or forearm is treated for a specified time, after which the material of interest remaining on the skin is removed. Absorption is measured by assessing changes in plasma or urine concentration over time or from stratum comeum concentrations in tape stripping samples [82, 92]. Other methods of detection have been employed and will be discnssed. 

Fig. 5 Urine (dashed line) and plasma (continuous line) concentrations over time of the pyrrolylphenyl mannoside 42f after an application of a dose of 10 mg kg (PBS containing 5% DMSO and 1% Tween 80). Shown are mean values with standard error of the mean for groups of three mice (C3H/HeN). The detection limit was at 0.02 pg mt ...

Plasma dmg concentrations rise at a gradual, controlled rate after dosing, and reach a plateau at approximately 6 h after the first dose with minimal fluctuations over the 24 h dosing interval. Subsequent doses maintain the plasma concentration at this plateau. The extended release tablets taken once daily have reduced by fourfold the fluctuations (ratio of peak to trough plasma concentration) observed with the conventional immediate release Procardia tablets taken three times daily (81). 

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