Talniflumate

Determination of talniflumate and niflumic acid in human plasma by liquid chromatography-tandem mass spectrometry.[Pubmed:19359802]

Anal Sci. 2009 Apr;25(4):571-4.

A simple and rapid quantification method was developed for determining both Talniflumate and niflumic acid in human plasma. After simple protein precipitation with acetonitrile, the analytes were chromatographed on a reversed-phase C(18) column and detected by LC/MS/MS with electrospray ionization. The assay accuracy and precision were within the FDA guidance for the analytical method validation. This method was used to measure the plasma concentrations of both compounds from healthy subjects after a single oral dose of Talniflumate, 740 mg.

Contribution of pH to systemic exposure of niflumic acid following oral administration of talniflumate.[Pubmed:21327911]

Eur J Clin Pharmacol. 2011 Apr;67(4):425-428.

PURPOSE: Systemic exposure to niflumic acid was significantly increased when Talniflumate was given orally together with a meal. To clarify the underlying mechanism, an in vitro dissolution study of Talniflumateonducted at different pH values, and magnesium hydroxide was co-administered in healthy volunteers. METHODS: In vitro dissolution tests of Talniflumate tablets were performed in a USP Paddle apparatus at pH 1.2, 4.0, and 6.8, respectively, in the presence and absence of Tween 80 (2%). Serial samples of the Talniflumate solution were taken and analyzed on a high-performance liquid chromatography (HPLC)/ultraviolet system. Healthy volunteers were divided randomly into two groups, and each volunteer received a single 740-mg dose of Talniflumate, with or without 1 g of magnesium hydroxide, following an overnight fast. The plasma concentrations of niflumic acid were measured using HPLC coupled with tandem mass spectrometry. RESULTS: Talniflumate was completely insoluble at each of the tested pHs in the absence of Tween 80. The drug was slowly and steadily dissolved (54%) at pH 4 in the presence of the surfactant, but the extent of dissolution was only 15 and 0.5% at pH 1.2 and 6.0, respectively. Magnesium hydroxide co-administered with Talniflumate significantly increased systemic exposure to niflumic acid: the mean maximum plasma concentration (C (max)) and area under the concentration-time curve (AUC (inf)) were augmented by 2.0- and 1.9-fold, respectively, compared with those in the absence of the antacid. Magnesium hydroxide significantly accelerated the appearance of niflumic acid in plasma by 2.8-fold. CONCLUSIONS: Magnesium hydroxide increases the rate and extent of systemic exposure to niflumic acid owing to the enhanced solubility of Talniflumate and absorption of niflumic acid. The possible combination of Talniflumate and an antacid should be considered in the development of pharmaceutical formulations.

Liquid chromatography-mass spectrometric method for the sensitive determination of niflumic acid in human plasma and its application to pharmacokinetic study of talniflumate tablet.[Pubmed:19010744]

J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Dec 15;876(2):159-62.

A sensitive LC-MS method was developed and validated for the determination of niflumic acid (NFA), the active metabolite of the Talniflumate formulation, in human plasma. The analyses were performed on C(18) column using acetonitrile-ammonium acetate buffer (pH 5.7, 40:60) as a mobile phase with quadrupole MS detection of NFA at m/z 281 in a negative ion-monitoring mode. Calibration curve was linear in the concentration range of 1-1000ng/mL in human plasma. The higher sensitivity of LC-MS allowed low concentrations of NFA to be determined at initial drug absorption and terminal elimination phases following oral administration of Talniflumate tablet.

Pharmacokinetic comparison of two formulations of talniflumate 370 mg tablets in healthy Korean volunteers.[Pubmed:27879193]

Int J Clin Pharmacol Ther. 2017 Jan;55(1):102-108.

BACKGROUND: Talniflumate, a prodrug of niflumic acid, is a potent analgesic and anti-inflammatory drug that has been widely used for the treatment of rheumatoid diseases. OBJECTIVE: The aim of this study was to compare the pharmacokinetics and to evaluate the bioequivalence of two formulations of Talniflumate 370 mg tablets (test formulation: Flumagen^(R) 370 mg tablet; reference formulation: Somalgen^(R) 370 mg tablet). METHODS: A randomized, open-label, single dose, two-sequence, two-period crossover clinical study was conducted. After oral administration of the study drug in each period, blood samples were collected up to 15 hours post-dose. The plasma concentration of niflumic acid, a metabolite of Talniflumate, was determined using HPLC-MS/MS. The pharmacokinetic parameters were estimated by non-compartmental method. RESULTS: The maximum plasma concentration (Cmax) and area under the concentration-time curve from zero to the time point with the last measurable concentration (AUClast) for the test formulation were 290.7 +/- 199 microg/L and 1,154 +/- 643 microgxh/L, respectively, and the corresponding values for the reference formulation were 286.8 +/- 193 microg/L and 1,151 +/- 577 microgxh/L, respectively. The geometric mean ratio and 90% confidence intervals (CI) of the test formulation to the reference formulation for the Cmax and -AUClast were 0.983 (0.829 - 1.166) and 0.979 (0.856 - 1.121), respectively. CONCLUSIONS: The pharmacokinetic profiles of the test and reference formulations were found not to be significantly different, meeting the Korean regulatory criteria for bioequivalence..

Talniflumate increases survival in a cystic fibrosis mouse model of distal intestinal obstructive syndrome.[Pubmed:16354791]

J Pharmacol Exp Ther. 2006 Apr;317(1):275-83.

Intestinal disease in cystic fibrosis (CF) mice closely mirrors aspects of obstructive syndromes in CF patients. The pathogenesis involves accumulation of mucoid debris in the crypts that fuse with intestinal content to form obstructing mucofeculant impactions. Treatment involves modalities that increase the fluidity of the luminal content, such as osmotic laxatives and liquid diets. We investigated the effects of Talniflumate (Lomucin, Genaera Corporation, Plymouth Meeting, PA), a compound that may be beneficial to treatment of CF intestinal disease based on three mechanisms of action: mucus synthesis inhibition by blockade of the murine calcium-activated chloride channel 3 (mCLCA3), nonsteroidal anti-inflammatory effects, and inhibition of Cl(-)/HCO (-)(3) exchanger(s) involved in intestinal NaCl absorption. Cohorts of CF mice were fed control diet or diets containing either Talniflumate (0.4 mg/g chow) or ibuprofen (0.4 mg/g chow) for 21 days to assess survival. Talniflumate significantly increased CF mouse survival from 26 to 77%, whereas ibuprofen had no effect (22% survival). Oral Talniflumate did not alter crypt goblet cell numbers or change intestinal expression of mCLCA3 but tended to decrease crypt mucoid impaction. Ussing chamber studies indicated that Talniflumate slightly increased the basal short-circuit current of CF intestine, but the change was not sensitive to secretagogue stimulation or bumetanide inhibition. In contrast, intracellular pH measurements of intact intestinal villous epithelium indicated that Talniflumate significantly inhibited apical membrane Cl(-)/HCO (-)(3) exchange by >50%. We conclude that oral Talniflumate increases the survival of CF mice, possibly by the beneficial effects of decreasing small intestinal NaCl absorption through the inhibition of apical membrane Cl(-)/HCO (-)(3) exchanger(s).