Drug accumulation calculation

Calculation of drug accumulation from the "average" plasma concentration... 

The observed or calculated fluctuation for a dosage regimen of a drug also depends solely on the chosen dosing interval and, like drug accumulation, it is also expressed by using the concept of a numerical value. 

The calculations in parts (f) and (g) support the theory that a smaller dose given more frequently will yield greater drug accumulation and smaller drug fluctuation, h. It has already been determined that administration of 300 mg aminophylline (equivalent to 237 mg theophylline), every 8h yields a peak steady-state theophylline plasma concentration of 14.44pgmL . The following equation allows determination of the loading dose (Di) necessary to attain this theophylline plasma concentration instantaneously. 

Poorly perfused tissues (adipose tissue, connective tissue, and bone) require hours to come into equilibrium with plasma drug concentrations (Fig. 25.1). Since the accumulation of anesthetic in body fat is relatively small soon after its IV administration, it is common clinical practice to calculate drug dosage on the basis of lean body mass rather than on total body weight. Thus, an obese patient may receive the same dose of IV anesthetic as a patient of normal body weight. 

Estimates of dosing rate and average steady-state concentrations, which may be calculated using clearance, are independent of any specific pharmacokinetic model. In contrast, the determination of maximum and minimum steady-state concentrations requires further assumptions about the pharmacokinetic model. The accumulation factor (equation [7]) assumes that the drug follows a one-compartment body model (Figure 3-2 B), and the peak concentration prediction assumes that the absorption rate is much faster than the elimination rate. For the calculation of estimated maximum and minimum concentrations in a clinical situation, these assumptions are usually reasonable. 

Tetrahydrocannabinol is metabolized in the liver to form active metabolites which are further metabolized to inactive polar compounds these are excreted in the urine. Some metabolites are excreted into the bile and then recycled via the enterohepatic circulation. Because of their high lipophilicity, most active metabolites are widely distributed in fat deposits and the brain, from which sources they are only slowly eliminated. The half-life of elimination for many of the active metabolites has been calculated to be approximately 30 hours. Accordingly, accumulation occurs with regular, chronic dosing. Traces of the cannabinoids can be detected in the blood and urine of users for many days after the last administration. There is some evidence of metabolic tolerance occurring after chronic use of the drug. THC and related cannabinoids readily penetrate the placental barrier and may possibly detrimentally affect foetal development. 

If a Biotech company does decide to sell its drug rather than develop it itself, what is the sensible expectation for a drug that will generate 1 billion per year Here the calculation is based on the accumulated value of the drug as it is developed. If you are a small company and you have only a single target, then you can get 100,000... 

In a drug discovery environment, the elimination rate is used to estimate accumulation after multiple dosing. Many terms of half-lives were introduced with the attempt to simplify multicompartment kinetics for the estimation of accumulation. A recent article by Sahin and Benet compared and commented on various terms of half-life [32], The accumulation after multiple dosing is not only a function of elimination rate but also a function of dosing interval for multicompartmental distribution compounds. In addition, the accumulation of Cmax is a function of absorption rate [32], Furthermore, the accumulation for Cmax, Cmin, and AUC can be different with the same compound and same dosing interval. Therefore, the half-life calculated based on accumulation ratios from different exposure parameters and with different dosing intervals for the same compound can be different. It is not practical to use... 

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