Plasma concentration-effect-time

These effects could result from the progression of the disease but as they are a feature of levodopa therapy a change in the central response to levodopa or changes in its peripheral kinetics are more likely. The latter does not occur since the maximum plasma concentration, the time to reach it and the plasma half-life are still similar after 10 years of treatment to those achieved initially, although continuous infusion of dopa can smooth out the swings. 

Figure 12.1 shows the plasma concentration versus time profile of an orally administered hypothetical drug. When the drug concentration in plasma equals the minimum effective concentration (MEC), therapeutic response is initiated. When the concentration exceeds the minimum toxic concentration (MTC), the drag causes toxic responses. Therefore, for ideal therapeutic response, the plasma concentration of drugs should be between the MEC and MTC. This region is called the therapeutic window. In Figure 12.1 the MEC is 1.5 ng/ mL, and the MTC is 3.5 ng/mL. The therapeutic window is between 1.5 and 3.5 ng/mL. 

If the minimum effective concentration is 3 mg/mL, what is the onset, intensity, and duration of action of the administered drug for which the following plasma concentration versus time data is available ... 

There may be several reasons for this pattern to be observed. One obvious reason is distribution, i.e. the drug needs time to reach its site of action, and the time lag between the measured drug concentration in plasma and the drug effect is due to distributional delay. In order to describe such a plasma concentration-effect relationship, a PK-PD model that allows for drug distribution to the site of action, e.g. the effect compartment model may be used. 

Freidman, H. et al., Pharmacokinetics and pharmacodynamics of oral diazepam effect of dose, plasma concentration, and time, Clin. Pharmacol. Ther., 52, 139, 1992. 

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. 

The effects of itraconazole on the pharmacokinetics and pharmacodynamics of oral prednisolone have been investigated in a double-blind, randomized, crossover study (98). Ten healthy subjects took either oral itraconazole 200 mg od or placebo for 4 days. On day 4 they took oral prednisolone 20 mg. Itraconazole increased the plasma AUC of prednisolone by 24% and its half-hfe by 29% compared with placebo. The peak plasma concentration and time to the peak of prednisolone were not affected. Itraconazole reduced the mean morning plasma cortisol concentration, measured 23 hours after prednisolone, by 27%. 

The effects of erythromycin, an inhibitor of CYP3A4, on the pharmacokinetics of lidocaine have been studied in nine healthy volunteers. Steady-state oral erythromycin had no effect on the plasma concentration versus time curve of lidocaine after intravenous administration, but erythromycin increased the plasma concentrations of the major metabolite of lidocaine, MEGX (78). It is not clear what the interpretation of these results is, particularly since the authors did not study enough subjects to detect what might have been small but significant changes in various disposition parameters of lidocaine and did not report unbound concentrations of Udocaine or its metabolites. However, whatever the pharmacokinetic explanation, the clinical relevance is that one would expect that erythromycin would potentiate the toxic effects of lidocaine that are mediated by MEGX. 

The effects of itraconazole, an inhibitor of CYP3A4, on the pharmacokinetics of lidocaine have been studied in nine healthy volunteers. Steady-state oral itraconazole had no effect on the plasma concentration versus time curve of lidocaine after intravenous administration nor on the plasma concentrations of the major metabolite of lidocaine, MEGX (78). 

Another situation in which the plasma concentration-effect relationship may be confounded by time is one where there is very rapid development of tolerance to the drug, even within a single dosing cycle. In this case, for a given plasma concentration, drug effect will be lower as concentrations are falling than when they are rising and will produce clockwise hysteresis this has been demonstrated for nicotine. 

Another factor associated with the adverse effects of oxybutynin IR, especially in older patients, is the transient high peak serum oxybutynin plasma concentration and area under the plasma concentration-versus-time curve (AUC), which is twofold higher in elderly patients than in younger adults, after both single and multiple doses. Oxybutynin IR is best tolerated when the dose is gradually escalated from no more than 2.5 mg twice daily to start, to 2.5 mg three times daily after... 

Effect of Basic Model Parameters on the Plasma Concentration versus Time Curve... 

The effects of different model parameters on the plasma concentration versus time relationship can be demonstrated by mathematical analysis of the previous equations, or by graphical representation of a change in one or more of the variables. Equation (10.95) indicates that the plasma concentration (Cp is proportional to the dose (Av) inversely proportional to the volume of distribution (V)- Thus an increase in Aw or a decrease in Fboth yield an equivalent increase in Cp as illustrated in Figure 10.20. Note that the general shape of the curve, or more specifically the slope of the line for ln(Cp versus t, is not a function of Av or V. Equations (10.98) and (10.99) show that the... 

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