Quantitative analysis of the farnesyl transferase inhibitor lonafarnib (Sarasartrade mark, SCH66336) in human plasma using high-performance liquid chromatography coupled with tandem mass spectrometry.
Lonafarnib is a novel anticancer drug that inhibits farnesyl transferase. To assess its pharmacokinetic properties, we developed a sensitive and quantitative assay using liquid chromatography coupled with tandem mass spectrometry for the determination of lonafarnib levels in human plasma. Sample pretreatment consisted of the addition of an isotopically labeled internal standard and protein precipitation with acetonitrile using 100 microL plasma. Chromatographic separation was performed on an Inertsil ODS-3 analytical column (50 x 2.1 mm i.d., particle size 5 microm) with acetonitrile/water/formic acid (50:50:0.05, v/v/v) as the mobile phase, at a flow rate of 0.2 mL/min. The analytical run time was 8 min. An API365 triple quadrupole mass spectrometer was used for specific and sensitive detection. It was operated in the positive ion mode and multiple reaction monitoring was used for drug quantification. The method was validated using a concentration range of 2.5 to 2500 ng/mL lonafarnib. Validation of the assay was performed according to the most recent FDA guidelines for bioanalytical method validation and all results were within the requirements. The described method was successfully applied to support a clinical phase I trial with lonafarnib.
Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. apnap@slz.nl
Natalie M G M
NM
Appels
Maria J
MJ
van Maanen
Hilde
H
Rosing
Jan H M
JH
Schellens
Jos H
JH
Beijnen
D000284:Administration, Oral; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D002851:Chromatography, High Pressure Liquid; D017321:Clinical Trials, Phase I as Topic; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000097:blood* / Q000737:chemistry / Q000627:therapeutic use; D051231:Farnesyltranstransferase; D006801:Humans; D007275:Injections, Intravenous; D015394:Molecular Structure; D017239:Paclitaxel / Q000627:therapeutic use; D010880:Piperidines / Q000097:blood* / Q000737:chemistry / Q000627:therapeutic use; D011725:Pyridines / Q000097:blood* / Q000737:chemistry / Q000627:therapeutic use; D015203:Reproducibility of Results; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D000068878:Trastuzumab; D003986:Dibenzocycloheptenes
D019883:Alkyl and Aryl Transferases; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D017239:Paclitaxel; D010880:Piperidines; D011725:Pyridines; D000068878:Trastuzumab; C115354:lonafarnib; D003986:Dibenzocycloheptenes