Useful pharmacokinetic parameters

The following are some of the most useful and fundamental pharmacokinetic parameters of a dmg. The knowledge of these parameters is. 

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For drugs that follow first-order kinetics, in addition to clearance, the half-life is a useful pharmacokinetic parameter to describe elimination. The elimination half-life (tj/j) is the time required for the concentration of drug to decrease by 50%. In clinical practice, this parameter is referred to as the plasma (or serum) half-life and is usually assessed by measuring the fall of... 

These animal models of disease should be considered early on as potentially providing some of the data necessary for initiation of human studies. Besides utility as proof of concept, they can add to understanding dose response as well as help evaluate some safety endpoints. New products resulting from improved manufacturing can be compared with previously produced material using pharmacokinetic parameters. 

Kanner AM, Bourgeois BF, Hasegawa H, Hutson P. Rapid switchover to carbamazepine using pharmacokinetic parameters. Epilepsia 1998 39(2) 194-200. 

Lack of favorable ADME properties (absorption, distribution, metabolism, elimination) can preclude therapeutic use of an otherwise active molecule. The clinical pharmacokinetic parameters of clearance, half-life, volume of distribution, and bioavailability can be used to characterize ADME properties. 

In practice, one will seek to obtain an estimate of the elimination constant kp and the plasma volume of distribution Vp by means of a single intravenous injection. These pharmacokinetic parameters are then used in the determination of the required dose D in the reservoir and the input rate constant k (i.e. the drip rate or the pump flow) in order to obtain an optimal steady state plasma concentration... 

Although most CF patients have shorter half-lives and larger volumes of distribution than non-CF patients, some patients exhibit decreased clearance. Possible causes include concomitant use of nephrotoxic medications, presence of diabetic nephropathy, history of transplantation (with immunosuppressant use and/or procedural hypoxic injury), and age-related decline in renal function in older adult patients. Additionally, CF patients are repeatedly exposed to multiple courses of IV aminoglycosides, which can result in decreased renal function. Evaluation of previous pharmacokinetic parameters and trends, along with incorporation of new health information, is key to providing appropriate dosage recommendations. 

Drugs can be cleared from the body by metabolism as well as renal excretion, and when this occurs it is not possible to measure directly the amount cleared by metabolism. However, the total clearance rate (TCR), or total body clearance, of the drug can be calculated from its pharmacokinetic parameters using the following equation ... 

The RCR can be determined from urine and plasma data using Eq. (18), and the TCR can be determined from the pharmacokinetic parameters using Eq. (19). Alternately, the RCR can be calculated by multiplying the TCR by the fraction of the dose excreted unchanged into urine,/), ... 

Other applications of the previously described optimization techniques are beginning to appear regularly in the pharmaceutical literature. A literature search in Chemical Abstracts on process optimization in pharmaceuticals yielded 17 articles in the 1990-1993 time-frame. An additional 18 articles were found between 1985 and 1990 for the same narrow subject. This simple literature search indicates a resurgence in the use of optimization techniques in the pharmaceutical industry. In addition, these same techniques have been applied not only to the physical properties of a tablet formulation, but also to the biological properties and the in-vivo performance of the product [30,31]. In addition to the usual tablet properties the authors studied the following pharmacokinetic parameters (a) time of the peak plasma concentration, (b) lag time, (c) absorption rate constant, and (d) elimination rate constant. The graphs in Fig. 15 show that for the drug hydrochlorothiazide, the time of the plasma peak and the absorption rate constant could, indeed, be... 

Coupling with its intravenous pharmacokinetic parameters, the extended CAT model was used to predict the observed plasma concentration-time profiles of cefatrizine at doses of 250, 500, and 1000 mg. The human experimental data from Pfeffer et al. [82] were used for comparison. The predicted peak plasma concentrations and peak times were 4.3, 7.9, and 9.3 qg/mL at 1.6, 1.8, and 2.0 hr, in agreement with the experimental mean peak plasma concentrations of... 

One of the most frequently used methods for predicting human pharmacokinetics from animal data is allometry. This technique was initially used to explain the relationship between body size and organ weights in animals [62-67]. The approach is based on finding a correlation between a physiological and the pharmacokinetic parameter of interest. Generally the relationship takes the form of ... 

The most useful pharmacokinetic variable for describing the quantitative aspects of all processes influencing the absorption (fa) and first-pass metabolism and excretion (Eg and Eh) in the gut and liver is the absolute bioavailability (F) [40]. This pharmacokinetic parameter is used to illustrate the fraction of the dose that reaches the systemic circulation, and relate it to pharmacological and safety effects for oral pharmaceutical products in various clinical situations. The bioavailability is dependent on three major factors the fraction dose absorbed (fa) and the first-pass extraction of the drug in the gut wall (EG) and/or the liver (EH) (Eq. (1)) [2-4, 15, 35] ... 

Once key pharmacokinetic parameters are estimated (based on population data) or calculated, they can be used to simulate the plasma concentrationtime profile of the drug for the patient and to ascertain how much drug to administer and when. 

Advances in techniques for chemical synthesis allow medicinal chemists to synthesize hundreds to thousands of compounds per month. Metabolic stability screening in liver microsomes is used extensively in early discovery to select the analogs or compounds most likely to have favorable pharmacokinetic parameters. This provides information on the relation of structure to stability, thus guiding synthesis strategies. 

Exposure is represented by pharmacokinetic parameters demonstrating the local and systemic burden on the test species with the test compound and/or its metabolites. The area under the matrix level concentration-time curve (AUC) and/or the measurements of matrix concentrations at the expected peak-concentration time Cmax, or at some other selected time C(llme, are the most commonly used parameters. Other parameters might he more appropriate in particular cases. 

The term clearance is used here in the sense of total body clearance and is analogous to the term renal clearance. The body as a whole is regarded as acting as a xenobiotic-eliminating system, where the rate of elimination divided by the average plasma concentration of the compound is the total body clearance. Here clearance is calculated (25) by dividing the administered dose of the substance by the area under the plasma concentrationtime curve produced by that dose. This pharmacokinetic parameter, as well as others presented in this publication, was calculated by the use of the MLAB on-line computer system established at the National Institutes of Health by Knott and Reece (26). Similar to t the total clearance is a composite of the individual clearances of the material by the various tissues of the body. 

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