Pharmacokinetics calculation

Method reproducibility — Individual incurred samples from four subjects (approximately 5% of all samples) were re-assayed individually to evaluate reproducibility. The four samples set for reanalysis and evenly spaced throughout the study were designated 101, 123, 145, and 166. The values generated from the reassays were used only to assess reproducibility and were not used in pharmacokinetic calculations. Table 2.2 summarizes the method reproducibility results. The analytical method used in study M06-830 was accurate, precise, and reproducible. 

Tricyclic antidepressants Despite the numerous publications over the past 30 years on the determination of the TCAs (Tricyclic Antidepressants) by HPLC to establish possible therapeutic windows, both therapeutic drug monitoring and pharmacokinetic calculations have revealed there is considerable variation (10- to 50-fold) in plasma concentrations between individuals with these drugs. The plasma concentrations are usually in the range of 50-300 ng/ml. 

The pharmacokinetic calculation of the unidirectional brain uptake rate, after intravenous injection, uses the relation of the brain concentration and the area under the curve of plasma concentration, AUC ... 

Case Example Pharmacokinetic Calculations to Interpret Phthalate Urinary Biomarker Data. The previous descriptions focused on blood or adipose biomarker concentrations that were converted to body burden to yield estimates of daily dose based on chemical half-life. A modified form of that is conversion of urinary biomarker data to daily exposure dose via simple model calculations as described for phthalates. 

Pharmacokinetic calculations yielded estimates of chlorpyrifos intake of 0.05-1 pg/kg per day in the general population. The model estimates compare favorably with pathway analysis estimates of aggregate chlorpyrifos exposure from numerous dose routes, including indoor inhalation, dermal contact, and food ingestion (Shurdut et al. 1998 Pang et al. 2002). The calculated exposure doses ranged from 0.02 to 1 pg/kg per day. Further... 

Bioanalytical study reports should describe the reason of repetition for each repeated sample. A table that lists each type of repeat is useful and facilitates straightforward and clear reporting. The table should include the original, repeat, and accepted result for use in pharmacokinetic calculations. To facilitate an understanding of the repeats as part of the overall study conduct, it is desirable to include the source of each result by listing the run ID for both the original and repeat results. Samples repeated in error (e.g., the analyst did not intend to repeat the sample) should also be reported. Furthermore, if no samples are repeated, the bioanalytical study report should include a statement in this regard. 

In cases where the study sponsor or pharmacokineticist5 assumes responsibility for selecting samples for repeat analysis, the bioanalytical laboratory should require and maintain written documentation of the request in the study file. The written documentation should identify the samples selected by the sponsor or pharmacokineticist, along with the basis for the selection. Ideally, the selection criteria used by the sponsor or pharmacokineticist should be provided to the bioanalytical laboratory in advance of sample analysis and maintained in the study file. Similarly, if the sponsor or pharmacokineticist assumes responsibility for determining the value reported for pharmacokinetic calculations, the SOP followed by the sponsor or pharmacokineticist in this regard should also be provided to the bioanalytical laboratory to facilitate a complete record for reconstructing the study conduct. 

Historically, vancomycin serum concentrations have been monitored and adjusted using first-order pharmacokinetic calculations (see aminoglycosides). However, difficulty obtaining a reliable peak concentration because of the initial distribution phase and lack of correlation between serum concentrations and efficacy and toxicity have led to a reappraisal of the value of pharmacokinetic monitoring with vancomycin. 

In performing pharmacokinetic calculations, we must take care to get the most precise answer that can be supported by the data we have. Conversely, we do not want to express our answer with greater precision than we are justified in claiming. The rules of significant figures will help us with this task. These are listed in Box 2.3. 

Be careful to retain at least 3 significant figures throughout all pharmacokinetic calculations and also to report numerical answers to 3 significant figures... 

A pharmacokinetic calculation is not complete unless both the number and the unit have been determined. If the unit that is determined is not the unit expected, this situation can evenalertyou too mistake in the calculation. For example, in a problem where a dose of drug is being calculated and the unit comes out to be something other than mass units, you would be well advised to perform the calculation again with particular care. 

In recent years, non-compartmental or model-independent approaches to pharmacokinetic data analysis have been increasingly utilized since this approach permits the analysis of data without the use of a specific compartment model. Consequently, sophisticated, and often complex, computational methods are not required. The statistical or non-compartmental concept was first reported by Yamaoka in a general manner and by Cutler with specific application to mean absorption time. Riegelman and Collier reviewed and clarified these concepts and applied statistical moment theory to the evaluation of in vivo absorption time. This concept has many additional significant applications in pharmacokinetic calculations. 

Sample preparation for each compound is performed in 96 well plate using a semiautomatic liquid handing station. LC-MS/MS instrumentation is used for the quantification of the sample and the final raw data are stored. Further calculation is done by appropriate quantification application. From the quantification, data concentration of unknowm samples are extrated and plotted versus the sampling time points (average plasma concentration vs. time). Pharmacokinetic calculations are performed by using pharmacokinetic software WinNonlin Pharsight Corporation) ... 

Space and the circulation. Depending on the drug, these compartments may need to be included in detailed pharmacokinetic calculations for patients with these disease states. 

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