Pharmacokinetics and Pharmacodynamics - Services

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Quantitation of anti-cancer agents and chemopreventive compounds in biospecimens:  Pharmacokinetic (PK) evaluation of anticancer agents requires highly sensitive analytical instruments for the quantitation of drugs in biospecimens including blood, plasma, urine, and tissue. Determination of pharmacokinetic parameters such as the area under the concentration-time curve (AUC), half-life, clearance, and volume of distribution require measurement of analytes in the biological samples. Quantitation of analytes in biological samples requires evaluation of the physical and chemical characteristics such as thermal stability, pKa, solubility, spectral characteristics of the analytes, and recovery from the sample with minimum loss. PK/PD personnel have utilized a variety of methods to improve the quantitative recovery of the analytes from different biospecimen matrices if tissue extraction has not previously been reported. The use of stable isotope labels can validate the extraction recoveries when necessary. The PK/PD shared resource includes all analytical instrumentation required for the quantitation of compounds and their metabolites including high performance liquid chromatography (HPLC), liquid chromatograph-mass spectrometry (LC-MS), as well as computers and software for data analysis.

Analytical method development: For analytes (drugs or metabolites) not previously described as being quantified in the literature or those that require a new method, PK/PD specialists will create a method based on their experience and/or adaptation from methods from other analytes with similar properties. Development of validated analytical methods for the quantitation of a drug in biological fluids and tissues generally requires a literature search, screening of columns, selection of solvents, identification of interfering compounds in the matrix, and baseline separation of the analyte/metabolites/internal standard in a single run in both HPLC and LC-MS assay. PK/PD Shared Resource successfully developed the quantitative methods of cyclophosphamide, busulfan, and sorafenib for Phase I/II clinical PK studies and ZMC1 in preclinical PK studies using LC-MS/MS.

Pharmacokinetic analysis: The drug concentration-time profile data are modeled by either applying parametric compartmental or noncompartmental models to determine PK parameters such as AUC, absorption, and elimination kinetics, t1/2, volume of distribution, and clearance, using WinNonlin software (Pharsight Corporation, Mountain View, CA) or ADAPT-5 software (USC). The PK/PD Shared Resource uses the Cancer Institute Biometrics Shared Resource for the statistical analyses of PK/PD data.

Pharmacodynamic analysis: Pharmacodynamic (PD) biomarkers are the indicators of drug effect on the target organism. PD biomarkers can be used to examine the relation between drug regimen and biological response. PD studies are of greatest importance in phase I/II studies evaluating investigational agents with novel mechanisms of action. PK/PD Shared Resource provides the service of Western Blot on PBMC, ELISA assay, γH2AX assay in CTCs for clinical and preclinical sample analysis.

 

 

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