Is Once‐Daily Mesalazine Equivalent to the Currently Used Twice‐Daily Regimen? A Study Performed in 30 Healthy Volunteers

Abstract

A randomized, 2-way, crossover study was conducted in 30 volunteers to compare the pharmacokinetic profile of a new once-daily dosing regimen of mesalazine (1 x 4 g/d) with the current twice-daily dosage (2 x 2 g/d) used in many European countries. The 2 dosages were administrated orally for 8 days, separated by a 2-week washout. Plasma concentrations of mesalazine and N-acetyl-mesalazine were determined on days 1 and 8 by a validated high-performance liquid chromatography method and C(max), t(max), and AUCs calculated. The bioequivalence was obtained for a 90% confidence interval of the AUC(0-24h) ratio (test/reference) for mesalazine and N-acetyl-mesalazine on days 1 and 8, within the range of 0.80 to 1.25. The bioequivalence was demonstrated on day 1 for mesalazine and N-acetyl-mesalazine and on day 8 for mesalazine. As it is desirable to offer patients a preparation with a less frequent administration to enhance compliance, this once-daily regimen may be an attractive dosing option.

Development and validation of a HPLC-ESI-MS/MS method for the determination of 5-aminosalicylic acid and its major metabolite N-acetyl-5-aminosalicylic acid in human plasma

“…plasma [16,[18][19][20][21][22][23], serum [24], feces [24], urine [18,19,[22][23][24], stones [25] and rectal biopsies [23,24]. These methods include HPLC combined with UV [16,[25][26][27], fluorescence (FL) [14][15][16]18,20,28,29], and electrochemical (EC) [21] detections. The preanalytical step for human plasma analysis includes protein precipitation with acetonitrile [15], methanol [21,26,28,30] or perchloric acid [14,16,29].…”

SIMDOT-AbMe: Microphysiologically Based Simulation Tool for Quantitative Prediction of Systemic and Local Bioavailability of Targeted Oral Delivery Formulations

“…Clinical literature data from Gandia et al (2007) were used to tune and validate the proposed model. A model consisting of one segment and five longitudinal compartments and a dosage regiment of 4 g of mesalamine, once daily, was used for tuning and validation.…”

“…The model was calibrated and validated using experimental data presented by Gandia et al (2007) for the systemic concentration of both the drug and metabolite. The clinical data (randomized, two-way, crossover study) compared the pharmacokinetic profile of a new once-daily dosing regimen of mesalazine (one 4-g/day dose) with the current twice-daily dosage (two 2-g/day doses) used in many European countries.…”

“…The effectiveness of the drug is related to its mucosal concentration and the fact that systemic dosages remain low after oral and rectal administration (Christensen et al, 1990;Frieri et al, 2000). Despite the drug's long history and numerous experimental and clinical studies on this group of medicines, the basic mechanism of action of 5-ASA is still the subject of extensive discussion (Gandia et al, 2007). The putative anti-inflammatory actions of 5-ASA include modulation of inflammatory cytokine production (Kaiser et al, 1999), decreased transcriptional activity of nuclear factor-B by modulating RelA/p65 phosphorylation (Egan et al, 1999), inhibition of the biosynthesis of prostaglandins and leukotrienes (Sharon et al, 1978;Lauritsen et al, 1985), inhibition of intestinal epithelial cell injury, and apoptosis induced by oxidative stress (Dallegri et al, 1990;Sandoval et al, 1997).…”

“…In fact, studies that assess the concentration of 5-ASA in the intestinal mucosa could provide direct evidence regarding adequate tissue concentrations of 5-ASA at the site of action. A lack of requirements by regulatory authorities and the absence of standard methodology for site and timing of tissue acquisition and issues regarding methods of gut preparation can significantly affect the result of local drug concentration measurements (Gandia et al, 2007). In addition, the use of existing general PK/PD mathematical models has only offered the standard PK parameters.…”