Plasma drug concentration pharmacokinetics

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. 

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. 

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. 

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.

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

FIG. 3-1. Single-dose plasma drug concentration versus time curves for the same dose of the same drug given to the same individual by three different routes. (From Janicak PG, Davis JM. Pharmacokinetics and drug interactions. In Sadock BJ, Sadock V, eds. Kaplan Sadock s comprehensive textbook of psychiatry, Vol. 2, 7th ed. Philadelphia Lippincott Williams Wilkins, 2000 2251, with permission. Artwork created by Matthew Janicak.)... 

Pharmacokinetic studies are in general less variable than pharmacodynamic studies. This is so since simpler dynamics are associated with pharmacokinetic processes. According to van Rossum and de Bie [234], the phase space of a pharmacokinetic system is dominated by a point attractor since the drug leaves the body, i.e., the plasma drug concentration tends to zero. Even when the system is as simple as that, tools from dynamic systems theory are still useful. When a system has only one variable a plot referred to as a phase plane can be used to study its behavior. The phase plane is constructed by plotting the variable against its derivative. The most classical, quoted even in textbooks, phase plane is the c (f) vs. c (t) plot of the ubiquitous Michaelis-Menten kinetics. In the pharmaceutical literature the phase plane plot has been used by Dokoumetzidis and Macheras [235] for the discernment of absorption kinetics, Figure 6.21. The same type of plot has been used for the estimation of the elimination rate constant [236]. 

Other sex-related differences in cardiovascular effect include the finding that antihypertensive drugs such as amlodipine exhibit greater antihypertensive effects in women than in men (119). Whether this greater response is due to differences in pharmacokinetics or pharmacodynamics is difficult to determine. Better blood pressure control could be explained by higher plasma drug concentrations in women, but pharmacokinetic differences do not necessarily correlate with the pharmacodynamic effects of antihypertensive drugs. 

FIGURE 30.2 Two-compartment model for peritoneal pharmacokinetics. Drug administered via a catheter is placed in the peritoneal cavity with a distribution volume of VpQ, yielding concentrations within the peritoneum of Cpc- Subsequent transfer betw een the peritoneum and the body compartment is mediated by diffusion with a permeability coefficient—surface area product of PA. CLp is the elimination clearance from the body. Plasma drug concentrations (Cp ) and systemic toxicity are minimized because the distribution volume of the body compartment (Vd) is much greater than VpQ and because CLp prevents complete equilibration of concentrations in the tw o compartments. (Adapted from Dedrick RL et al. Cancer Treat Rep 1978 62 1-11.)... 

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. 

The mean in vitro dissolution time is compared to either the mean residence time or the mean in vivo dissolution time. Level B correlation, like Level A correlation, uses all of the in vitro and in vivo data but is not considered to be a point-to-point correlation and does not uniquely reflect the actual in vivo plasma level curve, since several different in vivo plasma level-time curves will produce similar residence times. A Level C correlation is the weakest IVIVC and establishes a single point relationship between a dissolution parameter (e.g., time for 50% of drug to dissolve, or percent drug dissolved in two hours, etc.) and a pharmacokinetic parameter (e.g., AUC, Cmax, Tmax). Level C correlation does not reflect the complete shape of the plasma drug concentration-time curve of dissolution profile. 

Efficacy trials should not to be initiated until the MTD has been defined. In addition, the availability of pharmacokinetic information in healthy volunteers is key to the design of successful efficacy trials. The clinical pharmacokineticist assists in the design and execution of these trials and analyzes the plasma drug concentration data upon completion of the efficacy studies. 

Most beta-blockers undergo extensive oxidation (329). There have been anecdotal reports of high plasma concentrations of some beta-blockers in poor metabolizers of debrisoquine, and controlled studies have shown that debrisoquine oxidation phenotype is a major determinant of the metabolism, pharmacokinetics, and some of the pharmacological effects of metoprolol, bufuralol, timolol, and bopindolol. The poor metabolizer phenotjrpe is associated with increased plasma drug concentrations, a prolonged half-life, and more intense and sustained beta-blockade. There are also phenotypic differences in the pharmacokinetics of the enantiomers of metoprolol and bufuralol. 

The pharmacokinetics of intravenous levofloxacin have been studied in intensive care unit patients during continuous venovenous hemofiltration or hemodiafiltration (34,35). Levofloxacin clearance was substantially increased during both types of continuous renal replacement therapy. Levofloxacin 250 mg/day maintained effective plasma drug concentrations in these patients. 

The pharmacokinetics of a single intravenous injection of quinupristin + dalfopristin (7.5 mg/kg over 1 hour) have been assessed in 13 patients with severe chronic renal insufficiency (creatinine clearance 6-28 ml/minute/ 1.73 m ) (49). Although the mean peak plasma drug concentration and AUC of quinupristin plus its active derivatives and of both unchanged dalfopristin and dalfopristin plus its active derivatives were about 1.3-1.4 times higher than in healthy volunteers, the authors concluded that no formal reduction in the dosage of quinupristin + dalfopristin is necessary in patients with chronic renal insufficiency. 

The mean residence time is the equivalent of half-life and is the parameter calculated when non-compartmental methods are used to determine pharmacokinetic values. Some pharmacokinetic studies report mean residence time instead of half-life. The mean residence time is actually the time taken for the plasma drug concentration to decrease by 63.2% and should thus be somewhat greater than half-life. 

Limited pharmacokinetic data are available because saw palmetto is a mixture of various compounds (29). With respect to absorption of saw palmetto components, a mean peak plasma drug concentration of 2.6 mg/L of... 

Regardless of whether the data are analysed by a compartmental or non-compartmental method, the duration of blood sampling and the limit of quantification of the analytical method used to measure the drug concentration are important features of the pharmacokinetic study. The MRT, after an intravenous bolus dose of a drug can be estimated from either plasma drug concentration or urinary excretion data (Rowland Tozer, 1989). 

Fig. 4.1 Fundamental pharmacokinetic relationships for repeated administration of drugs. This figure depicts the plasma drug concentrations produced by administering maintenance doses at a constant dosage interval (equal to the half-life of the drug). A plasma concentration within 90% of the eventual steady-state concentration is attained after approximately four half-lives of the drug.

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