Development of quantitative methods for the determination of vemurafenib and its metabolites in human plasma
Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
Vemurafenib is a potent serine/threonine kinase inhibitor and is registered as Zelboraf® for the treatment of metastatic melanomas harboring BRAFV600E mutations. There is a large individual variation in drug response and the side effects observed among patients treated with Zelboraf® has proven to be severe.
LC-MS/MS methods were developed to measure vemurafenib and its metabolites in human plasma for prediction of treatment outcome and side effects in order to individualize treatment with Zelboraf®.
A novel, rapid quantification method was developed for vemurafenib using a stable isotope labeled internal standard. The method was validated according to international guidelines with regard to calibration range, accuracy, precision, carry-over, dilution integrity, selectivity, matrix effects, recovery and stability. All parameters met the set acceptance criteria.
The first method suitable for quantifying vemurafenib metabolites in human plasma is presented. Lacking commercially available reference substances, human liver microsomes were used to produce the metabolites. In patient samples at steady-state five previously in vitro identified metabolites were quantified for the first time.
Place, publisher, year, edition, pages
2014. , 50 p.
BRAFV600E, HPLC, Human Liver Microsomes, LC-MS/MS, Melanoma, Metabolites, Vemurafenib
Medical and Health Sciences Natural Sciences
IdentifiersURN: urn:nbn:se:liu:diva-110076ISRN: LITH-IFM-A-EX— 14/2938—SEOAI: oai:DiVA.org:liu-110076DiVA: diva2:742665
Subject / course
2014-05-27, Linden, Linköping, 13:00 (Swedish)
Vikingsson, Svante, Postdoctoral researcher
Josefsson, Martin, Docent, Forskningskemist