Application of a Reliable LC-MS/MS Method for Determination of Rizatriptan in Healthy Subject Samples: Demonstration of Assay Reproducibility by Incurred Sample Reanalysis
A reliable, rapid, and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay has been proposed for the determination of rizatriptan in human plasma using sumatriptan as internal standard (IS). The analyte and IS were extracted from 300？μL human plasma via liquid-liquid extraction and the chromatography was achieved on Hypurity C18 (50？mm × 4.6？mm, 5？μm) column under isocratic conditions. Detection of rizatriptan and IS was done by tandem mass spectrometry, operating in positive ionization and multiple-reaction monitoring mode. The limit of detection and lower limit of quantitation of the method were 0.04 and 0.20？ng/mL, respectively, with a linear dynamic range of 0.20–60.0？ng/mL. The intrabatch and interbatch precision (% CV) was ≤8.4% while the mean extraction recovery was >78% across quality control levels. Bench top stability, freeze and thaw stability, processed sample stability, and long-term stability in plasma were evaluated at two quality control levels. It was successfully applied to a bioequivalence study of 10？mg rizatriptan orally disintegrating tablet formulation in 40 and 32 healthy Indian male subjects under fasting and fed conditions, respectively. The reproducibility in the measurement of study data was demonstrated by reanalysis of 254 incurred samples. 1. Introduction Rizatriptan [RIZ, N,N-dimethyl-2-{5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl}ethanamin e] is a potent and selective 5-hydroxytriptamine 1B/1D (5-HT 1B/1D) agonist with a rapid onset of action, used for the acute treatment of migraine headache [1, 2]. The apparent mechanism of action of RIZ is done through activation of postsynaptic 5-HT 1B receptors within cerebral and dural vessel walls, causing vasoconstriction and inhibition of trigeminal perivascular nerve terminals [3, 4]. RIZ belongs to the second generation antimigraine drugs and is approved for the treatment of migraine at dose strength of 10 and 5？mg [5]. RIZ is completely absorbed after oral administration and shows mean oral bioavailability of ~45%. It undergoes extensive first-pass metabolism via monoamine oxidase-A and the mean plasma concentrations are reached in approximately 1 to 1.5？h. The half-life of RIZ in plasma is ~2？h and about 14% of an oral dose is eliminated unchanged in the urine. Approximately 50–60% of the administered dose is eliminated in the urine as the inactive indole-acetic acid metabolite. Although several minor metabolites have been identified, the N-monodesmethyl metabolite is pharmacologically active. As the plasma concentration of this metabolite is about
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