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Liquid Chromatography-Tandem Mass Spectrometry Method for Ticagrelor and its Active Metabolite Determination in Human Plasma: Application to a Pharmacokinetic Study

Author(s):

Niloufar Marsousi, Serge Rudaz, Jules A. Desmeules and Youssef Daali*   Pages 1 - 7 ( 7 )

Abstract:


BACKGROUND: Ticagrelor is a highly recommended new antiplatelet agent for treatment of patients with acute coronary syndrome at moderate or high ischemic risk. There is a real need of rapid and accurate analytical methods for ticagrelor determination in biological fluids for pharmacokinetic studies. In this study, a sensitive and specific LC-MS method was developed and validated for quantification of ticagrelor and its active metabolite (AM) in human plasma over expected clinical concentrations.

METHODS: Samples were handled by liquid-liquid extraction (LLE). A linear gradient was applied with a mobile phase composed of formic acid 0.1% and acetonitrile with 0.1% of formic acid using a C18 reversed-phase column. MS spectra were obtained by electrospray ionization in negative mode and optimized at 521.4→360.9 m/z, 477.2→361.2 m/z and 528.1→367.9 m/z transitions for ticagrelor, AM and ticagrelor-d7, respectively.

RESULTS: This method allowed rapid elution, in less than 4 minutes, and quantification of concentrations as low as 2 ng/mL for ticagrelor and 1 ng/mL for AM using only 100 µL of human plasma. LLE using hexane/ethyl acetate (50/50) was an optimal compromise in terms of extraction recovery and endogenous compounds interference. Trueness values of 87.8% and 89.5% and precisions of 84.1% and 93.8% were obtained for ticagrelor and AM respectively. Finally, usefulness of the method was assessed in a clinical trial where a single 180 mg ticagrelor was orally administered to healthy male volunteers. Pharmacokinetic parameters of ticagrelor and its active metabolite were successfully determined.

CONCLUSION: A sensitive and specific quantification LC-MS-MS method was developed and validated for ticagrelor and its active metabolite determination in human plasma. The method was successfully applied to a clinical trial where a single ticagrelor 180 mg dose was orally administered to healthy male volunteers. The described method allows quantification of concentrations as low as 2 ng/mL of ticagrelor and 1 ng/mL of the metabolite using only 100 µL of plasma.

Keywords:

Ticagrelor, LC-MS/MS, Quantification, Validation, Biological matrix

Affiliation:

Clinical Pharmacology and Toxicology Service, Geneva University Hospitals, School of pharmaceutical sciences, Geneva University, Clinical Pharmacology and Toxicology Service, Geneva University Hospitals, Clinical Pharmacology and Toxicology Service, Geneva University Hospitals



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