Plasma drug concentrations

Antidepressants are used in neuropathic pain and migraine prophylaxis. Tricyclics require monitoring of plasma drug concentrations to achieve optimal effect... 

Bioavailability is the amount of drug in a formulation that is released and becomes available for absorption or the amount of the drug absorbed after oral administration compared to the amount absorbed after intravenous administration (bioavailability - 100%), judged from areas remaining under plasma drug concentration-time curves. 

For an optimal therapeutic response, the clinical pharmacist must select a suitable drug and determine an appropriate dose with the available strengths and a convenient dosing interval. To meet this responsibility, the serum or plasma drug concentrations have to be analyzed, pharmacokinetic parameters have to be evaluated, the drug dose has to be adjusted, and the dosing interval has to be determined. 

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... 

Three correlation levels have been defined and categorized in descending order of the ability of the correlation to reflect the entire plasma drug concentration-time curve that will result from administration of a dosage form. The relationship of the entire in vitro dissolution curve to the entire plasma level curve defines the correlation. 

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. 

Lin, S. K., Su, S. F., and Pan, C. H. (2006) Higher plasma drug concentration in clozapine-treated schizophrenic patients with side effects of obsessive/compulsive symptoms. Ther. Drug Monit. 28, 303-307. 

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 ... 

Besides the poor specificity of many of the assays used to determine plasma drug concentrations, another problem which has arisen from these studies has been the length of the "wash-out" period necessary before the patient is given the neuroleptic under investigation. As a result of the prolonged duration of blockade of dopamine receptors in the brain by conventional neuroleptics and their metabolites, it is necessary to allow a wash-out period of several weeks before the patients are subject to a pharmacokinetic study. This raises serious ethical questions. Perhaps with the advent of new imaging techniques it may be possible in the near future actually to determine the rate of disappearance of neuroleptics from the brain of the patient. This may enable the relationship between plasma concentration and clinical response to be accurately determined. 

Over the past 20 years there has been widespread interest in monitoring plasma antidepressant, particularly tricyclic, levels to optimize the response to treatment. One aspect of this research that is universally agreed upon concerns the extensive interindividual variability among patients, but it is still uncertain whether a knowledge of the plasma drug concentration is of clinical value. 

Tamvakopoulos, C. S. Colwell, L. F. Barakat, K. Fenyk-Melody, J. GrifGn, P. R. et ah Determination of brain and plasma drug concentrations by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 2000, 14, 1729-1735. 

When a drug is administered orally, the plasma drug concentration depends on the distribution pathways. For example, if the drug is present in high concentration in the hepatic portal vein, the occurrence of the first-pass effect decreases the amount of drug that reaches the circulation. 

The Drug Delivery Index (DDI) ahows a quantification of the reduction in the drug dose and the systemic exposure observed after drug release specificahy to the colon [37]. It may be calculated using AUC (Area l/nder the plasma drug concentration-time Curve) data or drug concentrations in blood and colonic tissues under steady-state conditions ... 

Fig. 2.12 Receptor occupancy based on PET scanning and in vitro potency combined with free plasma drug concentration. Log D74 values shown below compound names.

Table I summarizes the percentages of sulfadimidine and its metabolites in the plasma of the different species Table II shows the tissue to plasma drug concentration ratios for SDM and its metabolites, while Table III presents the urinary recovery data (for poultry urinary plus faecal recovery). The metabolic pathways observed in various species are summarized in a scheme (Figure 2). Selected data obtained are illustrated in Figures 3-9.

Fig. 2.6 Effect of variation in absorption rate on plasma drug concentration. The graph shows simulated plasma concentration-time curves for theophyUine after oral administration, illustrating a 20% difference in Cpmax values resulting from variation in the absorption rate constant. Absorption rate constants top curve 2.2 per h (Cpmax 20 pg/mL) middle curve 1.0 per h (Cptnax 18 M-g/mL) bottom curve 0.7 per h. Note that tmax also changes. The established therapeutic concentration of theophyUin is 10-20 pg/mL. The most rapidly absorbed formulation produces the highest concentration and greatest chance of side effects. Also, the duration for which the plasma concentration is within the therapeutic range also varies. Pharmacokinetic parameters dose, 400 mg bioavaUabiUty, 0.8 volume of distribution, 29 L half-Ufe, 5.5 h.

The time evolution of plasma drug concentration can be treated by a simple model that assumes first-order absorption and first-order elimination of the drug. If [Dq] is the effective concentration of the drug dose, appearance of drug in the plasma will obey the relationship ... 

As shown above, the plasma drug concentration usually exhibits a biphasic rise and fall that are characteristic of all two-step series first-order processes. When k is zero, there will only be first-order absorption without any elimination, and when k > k, drug absorption will be virtually instantaneous, followed by first-order elimination. 

Absorption - Following oral administration immediately prior to a meal, nateglinide is rapidly absorbed with mean peak plasma drug concentrations (Cmax) generally occurring within 1 hour (T ax) f er dosing. Absolute... 

Pharmacokinetics Foscarnet is 14% to 17% bound to plasma protein at plasma drug concentrations of 1 to 1000 mcM. 

The volume of distribution is a parameter that can be calculated from plasma drug concentration versus time data (expressed as area under the curve or AUC), according to the two equations shown below, for terminal or steady-state volume of distribution, respectively. 

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