Pharmacokinetic studies stability validation

In addition, compound 15 also had good metabolic stability in human liver microsome in vitro assay (hLM ti/2 = 39min) and in rat in vivo pharmacokinetic studies (ty2 = 3.3 h, po), with a rat oral bioavailability of 15%, showing a significant improvement in these PK parameters over the lead compound 1. The observed improvement in PK during the optimization was another validation of the strategy discussed above. This part of the optimization process is summarized in Scheme 19.2. 

Analytical data generated in a testing laboratory are generally used for development, release, stability, or pharmacokinetic studies. Regardless of what the data are required for, the analytical method must be able to provide reliable data. Method validation (Chapter 7) is the demonstration that an analytical procedure is suitable for its intended use. During the validation, data are collected to show that the method meets requirements for accuracy, precision, specificity, detection limit, quantitation limit, linearity, range, and robustness. These characteristics are those recommended by the ICH and will be discussed first. 

The validated bioanalysis of rosuvastatin in human plasma by automated SPE in 96-well format with Oasis HLB material and positive-ion LC-ESI-MS-MS was reported using a [DJ-ILIS [54]. The stability of rosuvastatin and its potential conversion into the lactone due to sample pretreatment was thoroughly investigated. The method was applied in pharmacokinetic studies during clinical trials. A similar method was applied by the same group in the bioanalysis of the /V-desmethyl metabolite of rosuvastatin [55]. 

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