ABSTRACT
C17 is an orally available anti-tumor compound inhibiting cancer stem cell (CSC). In this study, a stable, sensitive and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established and validated, and was further applied to a pharmacokinetic study in nude mice receiving C17 by gavage. Using propranolol as the internal standard, the plasma samples were pre-treated by precipitation with methanol and analyzed on an Intersil C8-3 column (100 mm × 2.1 mm, 3 μm), and gradient elution was performed with a mobile phase consisting of 0.1% formic acid aqueous and solution mixed up by 90% isopropanol and 10% acetonitrile. The analyte was detected by a triple quadrupole tandem mass spectrometer, and multiple reaction monitoring was employed to select C17 at m/z 439.3/247.1 and propranolol at m/z 260.2/116.2 in the positive ion mode. The calibration curves were linear (r > 0.995) over the range of 5-800 ng·mL-1. The intra- and inter-day precisions and accuracies were 7.42%-13.22% and -8.99%-8.81% respectively. The method was successfully applied to a PK study in nude mice administered with a single oral dose of 50 mg·kg-1 C17, and the PK data were analyzed with non-linear mixed effect model (NONMEM). Two separated absorption peaks were found in the PK curve of C17, and a two-compartment model with two sequential first-order absorption rate was utilized to describe the PK properties of C17, and the model could provide insights into the physiological process and exposure of C17 in nude mice. All animal experiments were in strict accordance with the regulations of the Biomedical Ethics Committee of Peking University.
ABSTRACT
Models are simplified descriptions of true biological processes. Pharmacokinetic/pharmacodynamic (PK/PD) modeling is a mathematical description on the relationship between pharmacokinetics and pharmacodynamics. The PK/PD modeling allows estimation of PK/PD parameters and it can establish dose-concentration-response relationships which describe and predict the effect-time courses of a drug. PK/PD modeling has recently emerged as a major tool in clinical pharmacology in order to optimize drug uses by designing rational dosage forms. Population analysis is used to estimate the variability in the population and also to establish guidelines for the individualization of drug dosage regimen. Non-linear mixed effect model is the basis of population approach. This approach permits the simultaneous analysis for all the data of the studied population, by using either PK or PD models to describe the typical trends (population means) and individual profiles. The target controlled infusion system is based on the population PK models which describe the inter-individual PK variability by individualizing the PK parameters according to the patient's covariate. The PK/PD modeling is highly useful for the development of drugs as well as for pharmacotherapy.