@article{864d7b225f1d4af089f10d6b7145b16e,
title = "A sensitive and rapid liquid chromatography-tandem mass spectrometry method for the quantification of the novel neurokinin-1 receptor antagonist aprepitant in rhesus macaque plasma, and cerebral spinal fluid, and human plasma with application in translational NeuroAIDs research",
abstract = "A sensitive and rapid liquid chromatography-tandem mass spectrometry method has been developed for to assess therapeutic exposures of aprepitant in HIV-infected patients and rhesus macaques. The method utilized a simple sample-preparation procedure of protein precipitation with methanol. Chromatographic separation was performed on a reversed phase C8 column (Hypersil Gold, 50 mm × 2.1 mm, 3 μm) using a mobile phase composed of acetonitrile and water in 0.5% formic acid through gradient elution. Electro-spray ionization in positive mode was incorporated in the tandem mass spectrometric detection. The lower limit of quantitation of aprepitant in plasma of rhesus macaques and human and cerebral spinal fluid of rhesus macaques were 1, 1, and 0.1 ng/mL, respectively. The method has been successfully employed to measure aprepitant in preclinical and clinical samples collected from three SIV-infected rhesus macaques and ten patients with HIV infection. In conclusion, this liquid chromatography-tandem mass spectrometry method is suitable for preclinical-clinical translational research exploring exposure-response relationships with aprepitant as well as therapeutic drug monitoring of aprepitant.",
author = "Di Wu and Paul, {Dustin J.} and Xianguo Zhao and Douglas, {Steven D.} and Barrett, {Jeffrey S.}",
note = "Funding Information: Aprepitant (Emend {\textregistered} ), a neurokinin-1 receptor (NK-1R) antagonist, is licensed by the United States FDA as an antiemetic against chemotherapy-induced emesis and marketed by Merck & Co. in 2003. Currently, aprepitant is also being evaluated as a new therapy in NeuroAIDS patients from the Integrated Preclinical and Clinical Program (IPCP) grant mechanism supported by the NIH at the Children's Hospital of Philadelphia and University of Pennsylvania [2,3] . Developing sensitive bioanalytical methods to detect the exposure of aprepitant and its metabolites in biological fluids (e.g., plasma, cerebral spinal fluid [CSF]), is crucially important to facilitate pharmacokinetics and pharmacodynamics study in cell culture, simian immunodeficiency virus (SIV) infected rhesus macaques, and HIV-infected patients. Quantitation of aprepitant in human plasma has been reported using liquid–liquid extraction and HPLC-MS/MS with atmospheric-pressure chemical ionization (APCI) mass spectrometric detection [4,5] . In both of the published methods, the lower limit of quantitation (LLOQ) of aprepitant was reported as 10 ng/mL in human plasma [4,5] . In order to better characterize aprepitant in rhesus macaque CSF and human plasma, we incorporated protein precipitation and HPLC-MS/MS with electrospray ionization technique to develop a more sensitive and rapid bioanalytical method to quantify aprepitant in CSF and plasma. Our assay was validated in the concentration range of 0.1–10 ng/mL in CSF and 1–1000 ng/mL in plasma of rhesus macaque and human, respectively. Compared with traditional aprepitant sample-preparation procedures [4,5] , including liquid–liquid extraction, nitrogen blowing-down, and reconstitution with mobile phase, time duration and efforts for sample preparation in our assays was dramatically reduced by using a simple protein precipitation procedure, which is more suitable for preparing infectious samples from HIV-infected patients in hospitals and other clinical research laboratories. This method can be applied to therapeutic drug monitoring of aprepitant in clinics. Funding Information: We thank Dr. Pyone Aye for providing plasma and CSF samples obtained from control and SIV-infected rhesus macaques in aprepitant preclinical study at the Tulane National Primate Research Center, Dr. Pablo Tebas for supporting us with human plasma samples obtained from HIV-infected patients being treated with aprepitant in a phase IB, placebo controlled, double blind trial held at University of Pennsylvania School of Medicine, Dr. Florin Tuluc for kindly providing aprepitant standards for this analysis work. This work was supported by NIH Grant, P01 MH076388.",
year = "2009",
month = apr,
day = "5",
doi = "10.1016/j.jpba.2008.12.005",
language = "English (US)",
volume = "49",
pages = "739--745",
journal = "Journal of Pharmaceutical and Biomedical Analysis",
issn = "0731-7085",
publisher = "Elsevier B.V.",
number = "3",
}
