Pharmacodynamic pharmacokinetic analysis samples

Samples of blood and excreta are taken for laboratory analysis. It is expected that, at the end of this phase, you will have a preliminary estimate of the maximum dose that may be safely tolerated in humans, and also a basic profile of the drug s pharmacokinetic behaviour. Depending on the availability of appropriate analytical indicators, pharmacodynamic and indicative efficacy data may also be generated. The data acquired must be carefully analysed and assessed so that, based on the findings, appropriate Phase II trials can be planned. 

The analysis of samples obtained from physiological matrices has been the object of many reports on the use of Rlk]. This use can be expected to expand in response to the need to understand the pharmacodynamics and pharmacokinetics of various pharmaceutical agents. In addition, the versatility of RPC will facilitate the analysis of various metabolites and,... 

CPA and its deoxy analogues were further used in in vivo experiments [50]. The purpose was again to establish the relationship between blood concentration and the effect on heart rate in conscious, normotensive rats for the four compounds. The pharmacokinetics and pharmacodynamics were determined after a single intravenous infusion of each substance by monitoring the reductions in both heart rate (Fig. 6) and blood pressure (data not shown) and taking serial arterial blood samples for analysis of drug concentration. 

As the compound reaches the late discovery and candidate selection stage, the focus is to determine its major metabolic pathways, metabolic difference between species, and to identify potential pharmacologically active or toxic metabolites. Because of the complexity, comprehensive metabolite characterization studies have been typically conducted at this stage with radiolabeled standard. Identification of circulating metabolites is also important at this stage to explain the pharmacokinetic or the pharmacodynamic profile. An NCE may show efficacy that is inconsistent with what is predicted based upon the known concentration of the parent drug. These inconsistencies could be due to the presence of active metabolites. The knowledge of these metabolites will also dictate how the analysis of samples will be conducted in the development and clinical studies. 

Table 1.10 presents a sample table of contents for a modeling report used in support of a pharmacokinetic-pharmacodynamic analysis. The order of the report follows that of a scientific paper introduction, methods, results, and discussion. Within each section, the relevant aspects related to the model are presented. For example, within the discussion section, how plausible the model is,... 

Linear mixed effects models are primarily used in pharmacodynamic analysis or in the statistical analysis of pharmacokinetic parameters. Linear mixed effects models could also be used to analyze concentrationtime data from a 1-compartment model with bolus administration after Ln-transformation. The advantages to using mixed effects in an analysis are that observations within a subject may be correlated and that in addition to estimation of the model parameters, between- and within-subject variability may be estimated. Also, the structural model is based on the population, not on data from any one particular subject, thus allowing for sparse sampling. Most statistical packages now include linear mixed effects models as part of their analysis options, as do some pharmacokinetic software (Win-Nonlin). While linear mixed effects models are not cov-... 

Hing, J.P., Woolfrey, S.G., Greenslade, D. and Wright, P.M.C. Is mixed effects modeling or naive pooled data analysis preferred for the interpretation of single sample per subject toxicokinetic data. Journal of Pharmacokinetics and Pharmacodynamics 2001b 28 193-210. 

In addition to these qualitative studies, quantitative bioanalysis, e.g., in preclinical and clinical studies to provide pharmacokinetic and pharmacodynamic data, is an essential part of drug development. Quantitative bioanalysis is the most important application area of LC-MS, in terms of number of instruments applied and the number of analyses performed. Fast, high-throughput, and routine quantitative analysis by LC-MS also demands fast and automated sample pretreatment strategies and advanced data-processing software. 

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