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PHARMACOKINETICS |
From the Laboratoire de Pharmacocinétique et Toxicologie Clinique, Institut Fédératif de Biologie, Hôpital Purpan, Toulouse, France (Dr Gandia, Dr Houin); Ferring SAS, Gentilly, France (Dr Idier).
Address for reprints: Address for correspondence: Peggy Gandia, PharmD, PhD, Laboratoire de Pharmacocinétique et Toxicologie Clinique, Institut Fédératif de Biologie, Hôpital Purpan, TSA 70034, 330 avenue de Grande Bretagne, 31059 Toulouse cedex 9, France.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Mesalazine • bioequivalence • oral administration
, and inhibits the production of proinflammatory transcriptor factor (NF
B).10,11 An agonist effect on peroxisome proliferators-activated receptor- was recently described.12 However, it appears that the topical effect on the large bowel mucosa is more important than the systemic one,7,13-15 and thus, the local delivery of adequate concentration appears critical. Many factors16 (a variation of the gastrointestinal pH inducing a degradation of the drug, a decrease in the gastric emptying time, an accelerated intestinal transit time, or the food/beverage/drug coadministration) may decrease this local concentration, but at the present time, it is not clear if they do so significantly. For example, in a study performed by Yu et al,17 a high-fat breakfast reduced the relative systemic relative bioavailability of 5-ASA to 44% compared with the fasting state in 24 healthy volunteers who received 1 mg 5-ASA suspension, but no data were provided on the local concentration in the 2 states. Most patients with IBD have to ingest high doses of 5-ASA as remission maintenance therapy for several years.18 Therefore, it becomes difficult for many patients to comply with high daily intake using several-times-daily administration. Compliance is seldomly reached; a 40% overall adherence rate was found in a maintenance ulcerative colitis treatment with mesalazine.19 Consequently, compliance is the major goal in IBD, especially because the treatment may last several weeks or longer. It is known that an inverse relationship exists between the number of daily doses and the rates of compliance.20 Therefore, it is essential to offer patients a dose schedule that combines all the benefits of the well-established oral treatment with the advantages of a less frequent preparation to enhance patient compliance.
Sustained-release preparations with a local action, such as ethylcellulose-coated mesalazine, are by necessity more complicated than conventional tablets and capsules with a systemic action and require new methods for their evaluation.13,14,18,21,22 Indeed, studies that assess the concentration of mesalazine in the intestinal mucosa could provide more direct evidence of adequate tissue concentrations and site of action. However, it should be noted that studies of this nature are not currently required by regulatory authorities for product comparison.23 This is because there is no agreed standard methodology (for region of biopsy, gut preparation, or postdose biopsy timing) and because the interlaboratory reproducibility for any such tests is unknown.
Although the data available on the current mesalazine formulations with regard to colonic or mucosal levels are limited,13,14,22 an inverse relationship between the plasma AUC and the mucosal concentration of mesalazine and its main metabolite N-acetyl-mesalazine (N-ac-5-ASA) was reported by De Vos et al22 for the slow-release forms. These authors determined the intramucosal concentrations of 5-ASA and N-Ac-5-ASA in ileocolonic biopsy specimens from 61 patients with irritable bowel syndrome treated for 1 week with near equimolar doses of different slow-release preparations of 5-ASA (eudragit-coated mesalazine or ethylcellulose-coated mesalazine) or azo-bound drugs (sulfasalazine, olsalazine). Serum concentration-time curves over 8 hours were obtained from 34 healthy volunteers after a single oral dose of 400 to 500 mg depending on the form tested, and the plasma pharmacokinetics (Cmax, tmax, and AUC) were determined for 5-ASA and N-ac-5-ASA. Comparing the mucosal concentrations and the plasma AUC, the authors observed an inverse relation for slow-release preparations, which may be maintained whatever the intestinal transit time. Indeed, Christensen et al24 studied the influence of intestinal transit time on the release of 5-ASA from ethylcellulose-coated mesalazine in healthy volunteers. The authors reported a complete release of mesalazine in normal transit time conditions (24 hours) and a release of about 88% when the transit time was accelerated (5 hours) by a laxative, indicating that ethylcellulose-coated mesalazine is an acceptable source of 5-ASA in diarrheal states.
Taking into account the fact that the AUC of mesalazine is a good marker of the mucosal concentrations22 for slow-release preparations whatever the intestinal transit time,24 we performed a standard bioequivalence study to compare a once-daily regimen of 4 g of ethylcellulose-coated mesalazine with the current twice-daily regimen approved in many European countries (2 g of ethylcellulose-coated mesalazine twice a day [bid]) by repeated oral administration for 8 days. In addition to the determination of plasma mesalazine, plasma N-ac-5-ASA was also assayed. This metabolite, which does not show any pharmacological activity, is a good marker of the metabolism of mesalazine. Indeed, because of an extensive presystemic metabolism in the gut wall and in the liver, mesalazine reaches mean low plasma concentrations compared with N-ac-5-ASA.3,4,17,18,22,25,26
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Study Protocol
The clinical trial was conducted in a single study center (Aster S.A.S., Paris, France) and was an open, randomized, 2-way crossover study. Thirty-two healthy male subjects received repeated oral doses of mesalazine (ethylcellulose-coated mesalazine, Pentasa; Ferring SAS, Gentilly, France) from day 1 to day 8 according to 2 treatment schedules: 2 g bid (reference schedule: group A) or 4 g once a day (od; test schedule: group B). Each subject received the treatment in a randomized order (group A/B and group B/A). The 2 administration periods were separated by a 2-week washout period during which no mesalazine was taken, so as to prevent any carryover effect.
Subjects were required to attend the clinical unit in the morning of day 1 and day 8 at about 7 AM and remain resident under permanent medical and nursing supervision for 24 hours. From day 2 to day 7, subjects remained ambulatory and were asked to come to the clinical unit for dosing at about 8 AM. A fasting blood sample was taken for plasma drug determination. Before the morning administration, the volunteers were fasted for approximately 10 hours, and caffeine-free and alcohol-free beverages were permitted ad libitum, but only after the fourth hour postdosing, except for the 240 mL of mineral water administered simultaneously with the mesalazine. After drug intake, the subjects were asked to remain sitting or standing for 4 hours. On days 1 and 8, a standard lunch and dinner were served after the 4th and 13th hours following the morning dosing. On the day following administration of the last dose, subjects underwent a medical examination before returning home.
Blood sampling was performed on days 1 and 8, before administration (0) and 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 12.5, 13.0, 14.0, 16.0, 18.0, and 20.0 hours after morning dosing for the reference schedule (2 g x 2), with the second dose being taken at 12 hours. For the test schedule (4 g x 1), the times were before administration (0) and 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, 15.0, 18.0, and 21.0 hours after the morning dosing. Blood samples were collected into heparinized tubes and centrifuged at 1500g at 4°C for 10 minutes, and the plasma was aliquoted and stored in airtight stoppered polypropylene tubes at -20°C until assay.
The occurrence of adverse events (AEs) and changes in physical examination, vital signs (blood pressure and pulse rate), electrocardiogram (ECG), and clinical laboratory tests (biochemistry, hematology, urine levels of 
-glutathione S-transferase [-GST], N-acetyl-ß-D-glucosamidase [NAG], ß2-microglobulin, and protein) were determined during the screening period and at the end of the study.
Analytical Methods
Mesalazine and N-acetyl-mesalazine were measured in plasma by a simple and rapid high-performance liquid chromatography assay with fluorescence detection (Fluorimeter 474 Waters, 
excitation = 300 nm, emission = 418 nm), previously validated according to Arlington criteria.28 Briefly, 1 mL of plasma (spiked with 50 µL of internal standard, 4-amino-salicylic acid [4-ASA]) was extracted with 6 mL of diethylether. After evaporation of 5 mL of the ether phase under a gentle stream of nitrogen, the residue was dissolved in 1 mL of the reconstitution phase (850 mL acetate buffer 49 mmol/L pH = 4.8 and 150 mL acetonitrile) and 20 µL was injected into an analytical column (Ultrasphere IP Beckman, 5 µm, 250 x 4.6 mm). The mobile phase (flow rate = 0.8 mL/min) consisted of 1580 mL of acetate buffer 49 mmol/L and 420 mL of acetonitrile, and the pH was adjusted to 3.4 with 85% orthophosphoric acid. Mesalazine and N-acetyl-mesalazine eluted after 9.0 and 6.1 minutes, respectively.
The analytical procedure in human plasma was shown to be linear (weighting factor 1/X) from 20 ng/mL (lower limit of quantification) to 2500 ng/mL (upper limit of quantification). The intrabatch and interbatch precision and inaccuracy of the method were less than 9% for mesalazine and less than 7% for N-acetyl-mesalazine. The specificity of the method was verified against endogenous matrix components. The extraction recovery of the whole process was higher than 86% for mesalazine, higher than 72% for 5-acetyl-mesalazine, and higher than 86% for the internal standard. The dilution procedure (1/10) was shown to keep the precision and the inaccuracy within acceptable limits (±15%). The stability of mesalazine and 5-acetyl-mesalazine was demonstrated in human plasma after 3 freeze/thaw cycles (freezing at -24°C) and after storage at room temperature for 4 hours and in extracts after storage in the automatic injector at approximately +4° for 84 and 212 hours. The long-term stability in human plasma after storage in a freezer at -24°C was demonstrated for 1 month and 19 days for mesalazine and for 3 months for 5-acetyl-mesalazine.
Pharmacokinetic and Statistical Analysis
The interpretation of the drug time-concentration curves for each volunteer and for each treatment schedule (2 g x 2 and 4 g x 1) was performed with WinNonLin software (Pharsight Corporation, Champsur-Marne, France), using an independent-modeling calculation. For the calculation of the pharmacokinetic parameters of mesalazine and its metabolite, the following rules were applied: (1) the actual blood sampling time points were used; (2) in the lag time between time zero and the first concentration equal to or above the limit of quantification (LOQ), concentrations below the LOQ were recorded as zero; (3) concentrations below the LOQ between 2 concentrations equal to or above the LOQ were excluded; (4) concentrations below the LOQ were not used in calculations. The pharmacokinetic parameters measured for mesalazine and its metabolite were (1) AUC0-t, the area under the plasma concentration versus time curve from time 0 to the last measurable concentration (Clast), calculated using the trapezoidal method; (2) AUC0-
, the area under the plasma concentration versus time curve from time 0 (predose) to the time of dosing (12 or 24 hours), calculated using a trapezoidal method—after the bid dosing (2 g x 2, reference schedule), the AUC0- was calculated after the morning and the evening administrations; (3) AUC
, the area under the plasma concentration versus time curve from 0 to infinity, calculated as the sum of the AUC0-t + Clast/ke. ke is the first-order terminal rate constant calculated from a semilog plot of a plasma concentration versus time curve—2 criteria were imposed to calculate ke: the terminal data points were apparently randomly distributed about a single straight line (on visual inspection) and a minimum of 3 data points, including the last measured data point and excluding Cmax, were available for the regression; (4) t
, the terminal half-life calculated as ln(2)/ke; (5) Cmax and tmax, the maximum measured plasma concentration and the time to reach it, respectively; and (6) Frel, the relative bioavailability, calculated according to AUC0-24h(TEST)/AUC0-24h(REFERENCE).
All the descriptive statistics were performed on concentration data and pharmacokinetic parameters. Pharmacokinetic results were presented as the mean and the coefficient of variation (CV%).
The comparison between the 2 treatment schedules (2 g x 2 vs 4 g x 1) on day 1 and on day 8 was performed by comparing the AUC0-24h of mesalazine as the primary criterion and the AUC0-24h of its metabolite as the second criteria, using an analysis of variance followed by the calculation of the 90% confidence interval for the ratio test/reference as required by the European standard practice for a bioequivalence study.27 Values of the AUC were a priori log transformed with the aim of obtaining a distribution of the AUC according to the Gaussian curve and hence to perform parametric tests. It was concluded that there was no difference if the corresponding 90% confidence interval for the ratio of the means was between 0.80 and 1.25.27, 29
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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-GST, NAG, ß2-microglobulin, and protein) after dosing with the reference schedule were comparable with those after the test schedule, thus indicating that modification of the mesalazine regimen (4 g x 1 or 2 g x 2) had no effect on these specific markers of the renal function assessed in this study.
Pharmacokinetic Parameters of Mesalazine
The mean (±SD) plasma concentration-time curves of mesalazine and its metabolite, N-acetyl-mesalazine, obtained after 2 g x 2 mesalazine (reference schedule) or 4 x 1 mesalazine (test schedule) was administered for 8 days are shown in Figure 1 (day 1) and Figure 2 (day 8). The corresponding pharmacokinetic parameters are shown in Table II (day 1 and day 8) for mesalazine and in Table III (day 1 and day 8) for N-acetyl-mesalazine.
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The morning predose plasma concentrations of mesalazine were comparable between days 6 (918.09 ± 758.51 ng/mL and 493.82 ± 393.72 ng/mL), 7 (955.93 ± 812.90 ng/mL and 531.09 ± 404.72 ng/mL), and 8 (1047.39 ± 1197.79 ng/mL and 526.72 ± 382.23 ng/mL) for reference and test treatment schedules, respectively, thus indicating that steady state was reached on day 8, whatever the treatment.
On day 8, after repeated oral administrations of mesalazine, there was a rise in the Cmax of mesalazine and N-acetyl-mesalazine for both treatment schedules, which was slightly lower after the test treatment (4 g x 1) than the reference (2 g x 2). The ratio of the mean Cmax (day 8/day 1) was 1.33 and 1.14 for mesalazine and 1.15 and 1.04 for N-acetyl-mesalazine, after bid and od dosing, respectively.
The ratios of AUC0-24h(TEST)/AUC0-24h(REFERENCE) obtained on day 1 and day 8 for mesalazine and N-acetyl-mesalazine are reported in Tables II and III, respectively. For mesalazine, the 90% CIs were within the range of 0.80 to 1.25 on days 1 and 8. For N-acetyl-mesalazine, the ratio was included within the boundaries of 0.80 to 1.25 on day 1. By contrast, on day 8, the mean AUC0-24h after the reference schedule was significantly higher than the mean AUC0-24h after the test schedule, and the lower value of the 90% CI (0.77-0.88) was outside the range of 0.80 to 1.25.
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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For the reference schedule (2 g bid), on day 1, the mean pharmacokinetic parameters Cmax, tmax, and AUC0-24h were 5103.51 ng/mL, 2 hours, and 36 456 ng/mL•h, respectively, for 5-ASA and 5527.30 ng/mL, 2 hours, and 61 147 ng/mL•h, respectively, for N-ac-5-ASA. Our values are higher than those reported by other authors. Indeed, Bondesen et al26 studied the pharmacokinetics of mesalazine in healthy volunteers after the administration of a single intravenous bolus (100 mg and 250 mg) or a single slow-release formulation per os (250 mg, ethylcellulose-coated mesalazine). After oral administration, the authors reported a median lag time of 45 minutes (range, 15-150 minutes), a tmax of 4.0 hours (range, 1.5-5.0 hours), and a Cmax of 91.88 ng/mL (range, 61.26-214.40 ng/mL). Taking into account the difference of dosage with our study (250 mg once daily vs 2 g bid), after the oral administration of 2 g, Bondesen et al would have had to obtain a mean Cmax of 735.07 ng/mL to agree with our data. Similarly, Yu et al,34 after a single oral administration of 1 g ethylcellulose-coated mesalazine to healthy volunteers, reported a mean tmax of 3.5 hours and a mean Cmax of 995.41 ng/mL (mathematically corresponding to 1990.82 ng/mL after 2 g). For the metabolite N-acetyl-5-ASA, after a single oral administration of 250 mg of 5-ASA (ethylcellulose-coated mesalazine), Hardy et al21 reported a mean lag time of 0.72 hours, a mean tmax of 4.3 hours, and a mean Cmax of 380 ng/mL (mathematically corresponding to 3040 ng/mL for a dosage of 2 g) in healthy volunteers. Our values are higher than those reported by other authors, and this could be explained by a saturation of the oral absorption of mesalazine.
Mesalazine is absorbed through the intestinal wall by both active and passive mechanisms. Carriermediated transport of 5-ASA reaches saturation at a mucosal concentration of about 0.1 mg/mL35 and could be mediated by the intestinal organic transporter.36 For 5-ASA concentrations greater than 1 mg/mL (concentrations that are typically achieved by controlled-release dosage forms), the 5-ASA flux across the Caco-2 monolayer is independent of concentration, indicating that passive diffusion is more probable than carrier-mediated transport.35 Transepithelial 5-ASA transport at these high concentrations is most likely via the aqueous paracellular pathway rather than through lipid membrane permeation. Indeed, 5-ASA is a small (MW 154 D), predominantly anionic molecule (pKa1 2.3, pKa2 5.4) that possesses a low octanol-water and chloroform-water partition coefficient (logKp -1.4 and -1.5, respectively).35 Another factor that may explain our higher results is the presence of intestinal metabolism. Intestinal 5-ASA metabolism plays a key role in presystemic 5-ASA elimination at a concentration of 0.075 mg/mL.35 At this concentration, more than 60% of the 5-ASA loss from the intestinal lumen (11% of initial input concentration) is the result of intestinal metabolism with subsequent secretion of N-ac-5-ASA into the intestinal lumen. Consequently, when the transporter and the intestinal metabolism are saturated, a greater systemic absorption is obtained with a higher Cmax and AUC.16 Moreover, we observed a high intervariability (CV%) for the plasma concentrations and the pharmacokinetic parameters of mesalazine and its metabolite, as has been reported by other authors.14,21,26 With such different doses, it is thus unlikely that similar pharmacokinetic results would be seen between the different studies.
On day 1 and day 8, from the end of the absorption phase of mesalazine, the plasma concentrations of N-acetyl-mesalazine from both treatment schedules were higher than those of mesalazine, as reported by other authors.3,4,17,18,22,25,26 The particular profile of N-acetyl-mesalazine is due to the extensive presystemic metabolism of mesalazine in the gut wall and in the liver.
For mesalazine, on Day 1 and 8, the 90% CI of the ratio AUC0-24h(TEST)/AUC0-24h(REFERENCE) was within the range 0.80-1.25. For N-acetyl-mesalazine, on Day 1, the ratio was also in the range. By contrast, on Day 8, the ratio was 0.82 and the lower limit of the 90% CI (0.77-0.88) was outside the range. As this significant difference did not induce any adverse effect and as the pharmacological role of N-acetyl-mesalazine is not clearly identified in the treatment of IBD, this result does not exclude the bioequivalence between the two formulations.
Last, the clinical efficacy of the test schedule administered once daily between 2 administrations must be evaluated. The plasma concentrations of mesalazine were low from 12 hours until the next administration (ranging from 758.80 to 1118.56 ng/mL at day 1 and from 1252.31 to 17 48.98 ng/mL at day 8) compared with those obtained with the reference schedule. But they were above the steady-state plasma concentrations of mesalazine (200 ± 200 ng/mL)14 obtained with 1.5 g/d in patients with Crohn's disease and those (400 ± 100 ng/mL)14 obtained with 2 g/d in patients with ulcerative colitis. As the plasma concentrations of mesalazine obtained in our study from 12 to 24 hours were similar to those usually observed at the steady state in patients treated for IBD (taking into account the difference of dosage),14,37 we can conclude that the efficacy of the test schedule administered once daily in the morning should also be maintained during the night phase.
In conclusion, the present study clearly shows that a once-daily regimen of 4 g of ethylcellulose-coated mesalazine (od) did not induce any major AEs and is bioequivalent to the reference twice-daily regimen of ethylcellulose-coated mesalazine (bid) after single or repeated administrations. As it is essential to offer patients a schedule of administration that combines all the benefits of the well-established oral treatment with the advantages of a less frequent dosing to enhance patient compliance, this once-daily regimen may present an attractive dosing option with advantages for patients.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: This study was supported by Ferring S.A.S., France.
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REFERENCES |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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