The objectives were therefore (i) to characterize the population pharmacokinetics of total and free imatinib plasma concentrations, (ii) to evaluate the influence of both AGP and HSA concentrations in addition to demographic variables and co-medications on total and free imatinib pharmacokinetics inhibitor order us and (iii) to refine our model for the prediction of imatinib free concentrations based on total concentrations along with other potential influencing factors. Methods Study population Data from 49 GIST patients, providing a total of 150 plasma samples, were collected over 2 years (of these patients, three participated in our previous study [17], but no concentrations overlapped between the latter and this study). Patients received imatinib at daily oral doses ranging from 200 to 800 mg and all patients were pooled regardless of their medical history.
Most peripheral blood samples were drawn at 1�C6 month intervals on follow-up visits as part of an observational clinical pharmacokinetic study and of routine TDM laboratory tests for medical purposes. The median number of measurements for each patient was 3 (range 1�C11) and were obtained under steady-state conditions. The following data were recorded for each patient: body weight, gender, age, HSA and AGP concentrations (g l?1), as well as other administered drugs. ��1-acid glycoprotein concentrations measured twice in one patient during the same study day resulted in very different concentrations of AGP (0.7 and 1.99 mg l?1); these results were considered unreliable because of a possible degradation due to inappropriate storage and time interval until analysis, and were thus excluded from the covariate analysis).
Concomitant medications were categorized into inducers or inhibitors of the cytochromes (CYP) P450 3A4, mainly responsible for the metabolism of imatinib [10, 16]. In addition, proton pump inhibitors were recorded separately to test for a potential effect on imatinib absorption or relative bioavailability through an effect on gastric pH. The study was approved by the Ethics Committee of the Lausanne Faculty of Biology and Medicine. Informed written consent was obtained from all participants. Analytical equipment The high performance liquid chromatography system involved a Rheos 2200 binary pump (Flux Instruments, Basel, Switzerland) equipped with an online degasser and a temperature-controlled 324 vial autosampler maintained at +10��C (CTC Analytics AG, Zwingen, Switzerland).
The chromatographic system was coupled to a triple stage quadrupole mass spectrometer (TSQ Quantum Discovery; Thermo Carfilzomib Electron Corporation, Waltham, MA, USA) equipped with an electrospray ionization interface operated in positive ion mode and controlled with the Xcalibur 1.1 software (Thermo Electron Corporation, San Jose, CA, USA).