title: Laser diode thermal desorption atmospheric pressure chemical ionization tandem mass spectrometry applied for the ultra-fast quantitative analysis of BKM120 in human plasma.
abstract: A sensitive and ultra-fast method utilizing the laser diode thermal desorption ion source using atmospheric pressure chemical ionization coupled to tandem mass spectrometry (LDTD-APCI-MS/MS) was developed for the quantitative analysis of BKM120, an investigational anticancer drug in human plasma. Samples originating from protein precipitation (PP) followed by salting-out assisted liquid-liquid extraction (SALLE) were spotted onto the LazWell™ plate prior to their thermal desorption and detection by tandem mass spectrometry in positive mode. The validated method described in this paper presents a high absolute extraction recovery (>90 %) for BKM120 and its internal standard (ISTD) [D8]BKM120, with precision and accuracy meeting the acceptance criteria. Standard curves were linear over the range of 5.00 to 2000 ng mL(-1) with a coefficient of determination (R (2)) >0.995. The method specificity was demonstrated in six different batches of human plasma. Intra- and inter-run precision as well as accuracy within ±20 % at the lower limit of quantification (LLOQ) and ±15 % (other levels) were achieved during a three-run validation for quality control (QC) samples. The post-preparative stability on the LazWell™ plate at room temperature was 72 h and a 200-fold dilution of spiked samples was demonstrated. The method was applied successfully to three clinical studies (n = 847) and cross-checked with the validated LC-ESI-MS/MS reference method. The sample analysis run time was 10 s as compared to 4.5 min for the current validated LC-ESI-MS/MS method. The resultant data were in agreement with the results obtained using the validated reference LC-ESI-MS/MS assay and the same pharmacokinetic (PK) parameters were calculated for both analytical assays. This work demonstrates that LDTD-APCI-MS/MS is a reliable method for the ultra-fast quantitative analysis of BKM120 which can be used to speed-up and support its bioanalysis in the frame of the clinical trials.
authors: Novartis Pharma AG, DMPK/Bioanalytics, Forum 1 Novartis Campus, 4056, Basel, Switzerland.
authors: Christian
authors: C
authors: Lanshoeft
authors: Olivier
authors: O
authors: Heudi
authors: Luc Alexis
authors: LA
authors: Leuthold
authors: Götz
authors: G
authors: Schlotterbeck
authors: Walid
authors: W
authors: Elbast
authors: Franck
authors: F
authors: Picard
authors: Olivier
authors: O
authors: Kretz
mesh_terms: D000631:Aminopyridines / Q000097:blood*; D001272:Atmosphere; D001274:Atmospheric Pressure; D002138:Calibration; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002853:Chromatography, Liquid; D006801:Humans; D007834:Lasers; D016014:Linear Models; D059625:Liquid-Liquid Extraction / Q000379:methods*; D009025:Morpholines / Q000097:blood*; D010949:Plasma / Q000737:chemistry*; D011786:Quality Control; D012016:Reference Values; D015203:Reproducibility of Results; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry / Q000379:methods*; D013696:Temperature; D013997:Time Factors
chemical_list: D000631:Aminopyridines; D009025:Morpholines; C571178:NVP-BKM120