Plasma drug concentration measuring

Reynolds DJ, Aronson JK. 1993. ABC of monitoring drug therapy. Making the most of plasma drug concentration measurements. Br. Med. J. 306 48-51. 

Ideal for studying the dose-response relationship for QT interval prolongation taking into account all the pharmacological properties of a compound The dog model is one of the most widely used anesthetized rabbits (especially female rabbits) have also been proposed for high sensitivity It provides complementary information with respect to in vitro tests (activity of metabolites, measurement of plasma drug concentrations, calculation of the volume of distribution) Possibility to induce experimental TdP... 

Repeated dose chronic toxicity studies are performed on two species of animals a rodent and nonrodent. The aim is to evaluate the longer-term effects of the drug in animals. Plasma drug concentrations are measured and pharmacokinetics analyses are performed. Vital functions are studied for cardiovascular, respiratory, and nervous systems. Animals are retained at the end of the study to check toxicity recovery. Table 5.2 shows the duration of the animal studies, which depends on the duration of the intended human clinical trial. Appendix 6 summarizes the information to be submitted to regulatory authorities. 

Controversy still rages regarding the value of measuring the plasma drug concentrations of psychotropic drugs as a means of assessing the therapeutic response of the patient to treatment. A number of factors determine the value of such information. These include ... 

Again we will take blood samples at intervals after dosing, measure plasma drug concentrations, and plot the results on a linear graph (Fig. 11). The first and obvious thing to note is that the plasma concentrations rise to a maximum at around 1 h, whereas, of course, the early plasma concentrations taken soon after the intravenous bolus were the highest. The time to reach the peak plasma concentration after an oral dose is often abbreviated to Tmax, and the concentration itself to Cmax - the maximum concentration achieved after that dose. 

Measurement of drug concentrations in plasma is the cornerstone of therapeutic drug monitoring (TDM), but it is not without pitfalls. In many instances, clinical response does not correlate with plasma drug concentrations. Other considerations may be as follows. 

In the case of metoprolol succinate and metoprolol fumarate, the maximum drug concentration in the plasma( max) and the area under the plasma drug concentration-time curve were statistically equivalent, based on a 90% conLdence interval (Sandberg et al., 1993). With fenoprdffcQmthe following administration of its calcium salt was reached somewhat later thaCmjpassociated with the sodium form (Rubin et al., 1971). This was attributed to the slower dissolution rate for the calcium salt in acidic pH. Bioavailability and the measured distribution and elimination parameters, however, were reported to be similar. 

Routine monitoring of plasma concentrations of antidepressants, while technically feasible for most drugs, is of uncertain value (except for nortriptyline). However, studies suggest that at least 20% of patients become noncompliant at some time or other. Thus, a "poor response" in a patient for whom an adequate dosage of drug has been prescribed may be shown by measurement of the plasma drug concentration to be due merely to failure to take the drug. 

Blood is drawn as whole blood, that is, cells and plasma. Drug concentrations are measured in plasma, not whole blood. Whole blood is spun down in a centrifuge to allow separation of plasma from the cellular components. Plasma is more homogeneous than whole blood and therefore easier to analyze. The blood-to-plasma ratio of most drugs falls in a range of 0.5-1.5, and a value of 1 is generally not an unsafe assumption. In other words, the concentration of a drug in whole blood is often assumed to be the same as that... 

Therapeutic blood concentrations described in this chapter are based on studies that relate to drug concentrations measured at steady state of patients treated with recommended daily doses of a drug. However, the same dose of a drug can result in considerably different plasma concentrations in different individuals, depending on factors such as diet, lifestyle, comedication, and genetic makeup resulting in altered absorption, distribution, and elimination of drugs. 

Many drugs have distribution volumes that exceed expected values for TBW, or are considerably larger than ECF despite extensive binding to plasma proteins. The extensive tissue binding of these drugs increases the apparent distribution volume that is calculated by reference to drug concentrations measured in plasma water. By modifying Equation 3.1 as follows. 

Some authorities argue that it is improper to combine organ blood flow and -plasma concentrations in Equation 6.2 (7, 11). However/ in many cases the ratio of red cell/plasma drug concentrations remains constant over a wide concentration range so the same estimate of extraction ratio is obtained regardless of whether plasma concentrations or blood concentrations are measured. 

Many biochemistry laboratories no longer undertake routine measurement of the plasma concentration for most anticonvulsant drugs because plasma concentrations are insufficiently stable to serve as a useful guide to change of dose. The exception is phenytoin, where a small increase in dose may lead to a disproportionate rise in the plasma drug concentration (see zero-order pharmacokinetics, p. 99) and plasma monitoring is essential. With other drugs the dose is increased to the maximum tolerated level and, if seizures continue, it is replaced by another. 

DPI and three different doses using the EHD device. The nominal doses were 1000 pg for the DPI and 150, 250, and 400 pg for the EHD device. Multiple blood samples were collected from each subject up to 8 h after dosing to measure plasma drug concentration. An interval of 1 week was used between administration of the four doses. 

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