The Journal of International Medical Research 1990; 18: 441 - 4S3
Bioavailability of Single and Multiple Doses of Enteric-coated Mesalamine and Sulphasalazine A.E. Corey, G.M. Rose and J.D. Conklin Biopharmaceutics Section, Norwich Eaton Pharmaceuticals, Inc., Norwich, New York, USA
The bioavailibility of mesalamine from enteric-coated mesalamlne and sulphasalazine was determined following a single dose and at steady state in healthy subjects in crossover studies, Plasma concentrations and urinary excretion of mesalamiae and its major metabolite, N-acetyl-S-aminosalicylic acid, were measured. After a single dose of enteric-coated mesalamlne, about 10 h elapsed before the onset or measurable plasma drug concentrations, probably representinllU· tro-lntestinal transit prior to drug release near the i1eoeaecal junction. The elimination kinetics were similar for a single oral dose and steady state using enteric-coated mesalamine, but after both single and multi· pie administration of enteric-coated mesalamine only about 20% of the mesalamine given was absorbed, with about 80% estimated to remain for colon therapeutic activity. It is concluded that, _pitt different mechanisms of mesalamiae release, enteric-coated mftaIa· mine and sulphasalazine produced similar mesalamine absorptilm, KEY WORDS: Mesalamine; sulphasalazine; N-acetyl-5-ll.lIIinosalicyUc: acid; bknlvllilabllity; pharmacokinetics; Stl!lIdy state;healthyvolunteers.
INTRODUCTION
ulphasalazine is employedin the treatment of ulcerativecolitis 1 but its use is limited because of adverse reactions.s - •
S
Asacol" is a registered tradename of Norwich Ea.ton Pharmaceuticals, Inc., USA. Received for publication 15 August 1990; accepted 22 August 1990. Address for correspondence: Alfred E. Corey. ProductDevelopment Division. Norwich&ton Pharmaceuticals, Inc., PO Box 191, Norwich, New York, NY 13815, USA.
Within the colon sulphasalazine is ~plit by bacteria, releasing mesalamine (S~lUllinosaU· cylic acid) and sulphapyridine.5 Mesilla.mine has been shown to be the therapeutic moiety, whereas sulphapyrldine appear. to act as the carrier and is probably fe$ponsible for most of the side~effects.·,.6,7 As mesalamine is well abscrbed from the small intestine," it is neCe~slU'Y to use si»' cial dosage forms in order to deliver sub~ stantialamounts oforallyadministered druB to the colon. An enteric-coated mesalarnine tablet (Asacol'"), which provides de~ layed pH~dependent drugreleaseto achieve
© Copyright 1990by Cambridge MedicalPublications Ltd Downloaded from imr.sagepub.com by guest on August 4, 2016
441
A.E. Corey, G.M. Rose, J.D. Conklin
therapeutic activity in the colon, has an advantage over sulphasalazine in that it contains only mesalamine and delivers no sulphapyridine. Studies were undertaken to characterize the in vivo performance of the entericcoatedpreparation:a single-dosestudy (study 1) was carried out to show that delayed drug release with the desired poor absorption was achieved using this preparation; and study 2 was performed to evaluate its in vivo performance at steady state. The bioavailability and biological handling of mesalarnine from the enteric-coated preparation was compared to that of equimolar sulphasalazine doses in each study because sulphasalazine is routinely used to deliver mesalarnine to the colon in the treatment of ulcerative colitis. SUBJECTS AND METHODS
Subjects A total oBO healthy male volunteers, weighing between 59 and 84 kg, and aged between 18 and 40 years, were enrolled in study 1 and of these 29 subjects satisfactorily completed the study. In study 2, 30 healthy male volunteers, weighing between 60 and 79 kg, and aged between 18 and 37 years, were enrolled and 26 satisfactorily completed the study. For both studies, none of the subjects had any abnormalities of the central nervous, cardiopulmonary, gastro-intestinal, hepatic, renal, or haematopoietic systems, chronic or habitual drug or alcohol abuse, or a history of abnormal reaction or allergy to any drug. Each subject was also judged to be free of symptoms and exhibited no clinical laboratory parameters suggestive of disease that could affect drug absorption, distribution, metabolism, or excretion. In each study, concomitant medications were prohibited for 24 h prior to the start of each test period and for the duration of each test period. No beverages containing caffeine or alcohol were permitted during the studies.
Each of the study protocols were separately approved by an Institutional Review Board and written informed consent was obtained from each subject. Administration of therapy Study 1. Single oral doses of 800 mg mesalarnine were administered to each subject as two enteric-coated tablets and as four 500 mg sulphasalazine tablets using a randomized crossover design, a washout period of 12 days being maintained between each drug administration. All subjects fasted for 9 h prior and then received breakfast 1 h prior to drug administration. No fluids, other than water consumed when the drug was administered, were allowed 4 h after the drug had been taken; thereafter water was allowed ad libitum. Each subject received a standard lunch and dinner 4 - 5 and 9 -10 h, respectively, after drug administration, as well as a snack in the evening. All subjects were served the same menus at the same times in each test period. In each test period, blood samples were collected using 10 rnl evacuated blood collection tubes, with ethylenediarninetetraacetic acid as the anticoagulant, immediately before and 2, 4, 6, 8, 10, 12, 16,20, 24, 36, 48 and 60 h after drug administration. Following collection, the samples were immediately centrifuged and plasma isolated, and several 0.5 rnl plasma aliquots were frozen for subsequent drug analysis. A control urine specimen, with the bladder completely emptied, was also obtained from each subject just prior to drug administration in each test period and voided urine specimens were collected from 0 - 6, 6-12,12-24,24-36,36-48 and48-60 h after drug administration. At the completion of each collection interval, urine was pooled as necessary and the total urine volume was recorded. Several 0.1 rnl urine samples were immediately frozen for subsequent analysis.
442 Downloaded from imr.sagepub.com by guest on August 4, 2016
Bioavailability of enteric-coated mesalamine
Study 2. Oral doses of 800 mg mesalamine given as two enteric-coated tablets and as four 500 mg sulphasalazine tablets were administered to each subject at 12-h intervals on 11 consecutive occasions, using a randomized crossover design, with a washout period of 14 days being maintained between drug administration in the two test periods. The subjects fasted for 9 h and then received breakfast 1 h prior to each first dose of the drug given each day. No fluids, other than water consumed when the drug was taken, were allowed for 4 h after this first daily dose; thereafter water was allowed ad libitum. Each subject received a lunch and dinner 4 - 5 and 9 - 10 h, respectively, after each first daily dose, as well as a snack in the evening. The subjects were served the same menus at the same times in each test period. Blood and urine specimens were collected and processed as described for study 1. The blood collection times used were: day 1, before first dose; days 3 - 5, before and 6 and 12 h after the first daily dose; day 6, before and 2, 4, 6, 8, 10, 12, 14, 16,20, 24, 36, 48 and 60 h after drug dosage. The urine collection intervals used were: day 1, before first dose; day 3, before first daily dose; days 3 - 5, 0 - 6, 6 - 12 and 12 - 24 h after first daily dose; day 6, 0 - 6, 6 - 12, 12 - 24,24 - 36,36 - 48 and 48 - 60 h after drug dosage. High-performance liquid chromatography The concentrations of mesalamine and its metabolite, N-acetyl-5-aminosalicylic acid (NAS), in plasma and urine were determined using a modification of the method of Shaw et al? Plasma (0.5 ml) or 0.1 ml urine was mixed with 0.5 ml methanol containing the internal standard (50 mg or 300 mg 2,4-dihydroxybenzoic acid for plasma or urine, respectively) and centrifuged. The supernatant was analysed for mesalamine and its metabolite by highperformance liquid chromatography with fluorescence detection, using Waters Model
590 programmable solvent-delivering module, Waters WISP Model 710B autoinjector, Waters C18 ,uBondpak Guard Pak precolumn module, Caulab CSC PRP-110 ,urn, 0.41 em x 25 em column, and Kratos Spectroflow 980 fluor-escence detector (excitation wavelength 315 nm, emission wavelength 475 nm). The mobile phase consisted of 80% 0.05 M pot-assium phosphate buffer (pH 7.9) containing 0.1% tetrabutylammonium hydroxide, 10% methanol and 10% acetonitrile. Using a flow rate of 1.0 ml/min, approximate retention times of 3.3, 5.1 and 9.1 min were obtained for the internal standard, mesal-amine and NAS, respectively. Mesalamine and NAS concentrations in plasma and urine were calculated based on the peak height ratios of mesalaminel internal standard or NAS/internal standard for the specimens and using response factors from the daily standard curve. The calibration curves for mesalamine and NAS in plasma were linear (r > 0.992) over the ranges 0.025 - 1 and 0.05 - 2.5 ,ug/ml, respectively, and mean (± SD) recoveries of mesalamine and NAS from plasma were 103.4 ± 2.7% and 92.6 ± 5.2%, respectively. The mean (± SD) interassay precision of the plasma method for mesalamine over the two studies was 6.5 ± 2.2% and the accuracy was 100.0 ± 3.0%. For NAS the interassay precision of the plasma method over the two studies was 5.7 ± 2.1% and the accuracy was 97.6 ± 6.4%. For mesalamine and NAS method sensitivities were 0.025 and 0.05 ,ug/ml, respectively, in human plasma. The calibration curves for mesalamine and NAS in urine were linear (r > 0.993) over the ranges 1 - 20 and 10 - 200 ,ug/ml, respectively, and the mean (± SD) recoveries for mesalamine and NAS from urine were 90.4 ± 2.3% and 89.0 ± 2.0%, respectively. The mean (± SD) interassay precision of the urine method over the two studies for mesalamine was 6.1 ± 2.0% and the accuracy was 99.9 ± 4.4%. For NAS
443 Downloaded from imr.sagepub.com by guest on August 4, 2016
A.B. Corey, O.M. Rose. J.D. Conklin over the two studies the mean (± SO) inprecision of the urine method was 5.1 ± 1.9% and the accuracy was 96.9 ± 5.8%. The method sensitivities for mesalamine and NAS in human urine were 1 and 10 Jlg/ml, respectively. ~assay
Pharmacokinetic analysis Based on the variable release of drug that has been reported for dosage forms similar to enteric-coated mesalamine,S.IO-12 which is probably due to inter- and intrasubject variations in gastro-intestinal conditions, it was anticipated that complete pharmacokinetic characterizations might not be possible with the limited number of specimens that could be collected in these crossover studies. All calculations were performed using in-house programs. Maximum plasma drug concentration «;...), time to CItlllX• (tmax) , minimum plasma drug concentration (Cmin) and time until onset of measurable plasma drug concentration (t delay) were reported as observed. Area under the plasma drug concentration - time curve (AUC) from zero time to the last collection time was calculated by the trapezoidal rule, and AUe from zero to infinite time (AUC 0 _..) was calculated by extrapolation using the elimination rate constant. The plasma terminal half-life of drug elimination was calculated on the basis of the slope of the terminal loglinear portion of the plasma drug concentration - time profile, using only plasma concentrations greater than method sensitivity; a proprietary least-squares regression program was used for these calculations. Urine drug dose recovery (DR) was calculated by standard methods, which included an adjustment for the difference in molecular weight difference between mesalamine and NAS in the calculation of the urine DR for NAS. It has been reported that following administration of mesalamine, mesalamine and NAS detected in human plasma and urine by most analytical methods accounted
for all drug and known metabolites," and it has also been shown that there was very little biliary excretion of mesalamine and NAS,14.ls therefore the total amount of mesalamine absorbed could be determined by combining urine mesalamine and NAS DRs. Using an adjustment for the molecular weight difference between mesalamine and NAS, plasma mesalamine and NAS AUCs were combined to reflect total systemic availability of mesalamine.
Statistical analysis For both studies, comparisons of parameters were made using analysis of variance procedures; all analyses were two-sided and used a significance level of 0.05. In addition, for study 1 confidence intervals between treatment means were calculated at the 0.025 level using Sidak's method, to assure that the overall probability of a type I error in these comparisons was no more than 0.05. It should be noted that there was a large degree of intersubject variation, and as a result, only low statistical power to detect a 20% difference in the parameters could be attained, despite the relatively large subject populations used for each study. This situation was not entirely unanticipated and it was intended to determine meaningful differences and similarities in product performance on both a mean and individual subject basis. RESULTS
Study 1 The mean plasma mesalamine concentration - time profiles obtainedfollowing single oral 800 mg mesalamine doses as two enteric-coated tablets and as four 500 mg sulphasalazine tablets are shown in Fig. I and the corresponding plasma NAS concentration - time profiles are illustrated in Fig. 2. Mesalamine and NAS pharmacokinetic results for the two products are summarized in Table I, and combined plasma mesal-amine and NAS AUCs, as well as urine mesalamine and NAS DRs, are
444 Downloaded from imr.sagepub.com by guest on August 4, 2016
Bioavailability of enteric-eoated mesalamine
1.5
- t - - Enteric-coated masalamine - - >+- -
o
Sulphasalazine
20
40
60
Time (h)
Fig. 1. Mean (± SD) plasma mesaIamine concentrations in healthy volunteers after administration of a single oral 800 mg mesalamine dose as two enteric-coated tablets or as four 500 mg sulphasalazine tablets.
1.5
- t - - Enteric-coated masalamine -
-)Eo -
Sulphasalazine
1.0
~ -=
Bioavailability of Single and Multiple Doses of Enteric-coated Mesalamine and Sulphasalazine A.E. Corey, G.M. Rose and J.D. Conklin Biopharmaceutics Section, Norwich Eaton Pharmaceuticals, Inc., Norwich, New York, USA
The bioavailibility of mesalamine from enteric-coated mesalamlne and sulphasalazine was determined following a single dose and at steady state in healthy subjects in crossover studies, Plasma concentrations and urinary excretion of mesalamiae and its major metabolite, N-acetyl-S-aminosalicylic acid, were measured. After a single dose of enteric-coated mesalamlne, about 10 h elapsed before the onset or measurable plasma drug concentrations, probably representinllU· tro-lntestinal transit prior to drug release near the i1eoeaecal junction. The elimination kinetics were similar for a single oral dose and steady state using enteric-coated mesalamine, but after both single and multi· pie administration of enteric-coated mesalamine only about 20% of the mesalamine given was absorbed, with about 80% estimated to remain for colon therapeutic activity. It is concluded that, _pitt different mechanisms of mesalamiae release, enteric-coated mftaIa· mine and sulphasalazine produced similar mesalamine absorptilm, KEY WORDS: Mesalamine; sulphasalazine; N-acetyl-5-ll.lIIinosalicyUc: acid; bknlvllilabllity; pharmacokinetics; Stl!lIdy state;healthyvolunteers.
INTRODUCTION
ulphasalazine is employedin the treatment of ulcerativecolitis 1 but its use is limited because of adverse reactions.s - •
S
Asacol" is a registered tradename of Norwich Ea.ton Pharmaceuticals, Inc., USA. Received for publication 15 August 1990; accepted 22 August 1990. Address for correspondence: Alfred E. Corey. ProductDevelopment Division. Norwich&ton Pharmaceuticals, Inc., PO Box 191, Norwich, New York, NY 13815, USA.
Within the colon sulphasalazine is ~plit by bacteria, releasing mesalamine (S~lUllinosaU· cylic acid) and sulphapyridine.5 Mesilla.mine has been shown to be the therapeutic moiety, whereas sulphapyrldine appear. to act as the carrier and is probably fe$ponsible for most of the side~effects.·,.6,7 As mesalamine is well abscrbed from the small intestine," it is neCe~slU'Y to use si»' cial dosage forms in order to deliver sub~ stantialamounts oforallyadministered druB to the colon. An enteric-coated mesalarnine tablet (Asacol'"), which provides de~ layed pH~dependent drugreleaseto achieve
© Copyright 1990by Cambridge MedicalPublications Ltd Downloaded from imr.sagepub.com by guest on August 4, 2016
441
A.E. Corey, G.M. Rose, J.D. Conklin
therapeutic activity in the colon, has an advantage over sulphasalazine in that it contains only mesalamine and delivers no sulphapyridine. Studies were undertaken to characterize the in vivo performance of the entericcoatedpreparation:a single-dosestudy (study 1) was carried out to show that delayed drug release with the desired poor absorption was achieved using this preparation; and study 2 was performed to evaluate its in vivo performance at steady state. The bioavailability and biological handling of mesalarnine from the enteric-coated preparation was compared to that of equimolar sulphasalazine doses in each study because sulphasalazine is routinely used to deliver mesalarnine to the colon in the treatment of ulcerative colitis. SUBJECTS AND METHODS
Subjects A total oBO healthy male volunteers, weighing between 59 and 84 kg, and aged between 18 and 40 years, were enrolled in study 1 and of these 29 subjects satisfactorily completed the study. In study 2, 30 healthy male volunteers, weighing between 60 and 79 kg, and aged between 18 and 37 years, were enrolled and 26 satisfactorily completed the study. For both studies, none of the subjects had any abnormalities of the central nervous, cardiopulmonary, gastro-intestinal, hepatic, renal, or haematopoietic systems, chronic or habitual drug or alcohol abuse, or a history of abnormal reaction or allergy to any drug. Each subject was also judged to be free of symptoms and exhibited no clinical laboratory parameters suggestive of disease that could affect drug absorption, distribution, metabolism, or excretion. In each study, concomitant medications were prohibited for 24 h prior to the start of each test period and for the duration of each test period. No beverages containing caffeine or alcohol were permitted during the studies.
Each of the study protocols were separately approved by an Institutional Review Board and written informed consent was obtained from each subject. Administration of therapy Study 1. Single oral doses of 800 mg mesalarnine were administered to each subject as two enteric-coated tablets and as four 500 mg sulphasalazine tablets using a randomized crossover design, a washout period of 12 days being maintained between each drug administration. All subjects fasted for 9 h prior and then received breakfast 1 h prior to drug administration. No fluids, other than water consumed when the drug was administered, were allowed 4 h after the drug had been taken; thereafter water was allowed ad libitum. Each subject received a standard lunch and dinner 4 - 5 and 9 -10 h, respectively, after drug administration, as well as a snack in the evening. All subjects were served the same menus at the same times in each test period. In each test period, blood samples were collected using 10 rnl evacuated blood collection tubes, with ethylenediarninetetraacetic acid as the anticoagulant, immediately before and 2, 4, 6, 8, 10, 12, 16,20, 24, 36, 48 and 60 h after drug administration. Following collection, the samples were immediately centrifuged and plasma isolated, and several 0.5 rnl plasma aliquots were frozen for subsequent drug analysis. A control urine specimen, with the bladder completely emptied, was also obtained from each subject just prior to drug administration in each test period and voided urine specimens were collected from 0 - 6, 6-12,12-24,24-36,36-48 and48-60 h after drug administration. At the completion of each collection interval, urine was pooled as necessary and the total urine volume was recorded. Several 0.1 rnl urine samples were immediately frozen for subsequent analysis.
442 Downloaded from imr.sagepub.com by guest on August 4, 2016
Bioavailability of enteric-coated mesalamine
Study 2. Oral doses of 800 mg mesalamine given as two enteric-coated tablets and as four 500 mg sulphasalazine tablets were administered to each subject at 12-h intervals on 11 consecutive occasions, using a randomized crossover design, with a washout period of 14 days being maintained between drug administration in the two test periods. The subjects fasted for 9 h and then received breakfast 1 h prior to each first dose of the drug given each day. No fluids, other than water consumed when the drug was taken, were allowed for 4 h after this first daily dose; thereafter water was allowed ad libitum. Each subject received a lunch and dinner 4 - 5 and 9 - 10 h, respectively, after each first daily dose, as well as a snack in the evening. The subjects were served the same menus at the same times in each test period. Blood and urine specimens were collected and processed as described for study 1. The blood collection times used were: day 1, before first dose; days 3 - 5, before and 6 and 12 h after the first daily dose; day 6, before and 2, 4, 6, 8, 10, 12, 14, 16,20, 24, 36, 48 and 60 h after drug dosage. The urine collection intervals used were: day 1, before first dose; day 3, before first daily dose; days 3 - 5, 0 - 6, 6 - 12 and 12 - 24 h after first daily dose; day 6, 0 - 6, 6 - 12, 12 - 24,24 - 36,36 - 48 and 48 - 60 h after drug dosage. High-performance liquid chromatography The concentrations of mesalamine and its metabolite, N-acetyl-5-aminosalicylic acid (NAS), in plasma and urine were determined using a modification of the method of Shaw et al? Plasma (0.5 ml) or 0.1 ml urine was mixed with 0.5 ml methanol containing the internal standard (50 mg or 300 mg 2,4-dihydroxybenzoic acid for plasma or urine, respectively) and centrifuged. The supernatant was analysed for mesalamine and its metabolite by highperformance liquid chromatography with fluorescence detection, using Waters Model
590 programmable solvent-delivering module, Waters WISP Model 710B autoinjector, Waters C18 ,uBondpak Guard Pak precolumn module, Caulab CSC PRP-110 ,urn, 0.41 em x 25 em column, and Kratos Spectroflow 980 fluor-escence detector (excitation wavelength 315 nm, emission wavelength 475 nm). The mobile phase consisted of 80% 0.05 M pot-assium phosphate buffer (pH 7.9) containing 0.1% tetrabutylammonium hydroxide, 10% methanol and 10% acetonitrile. Using a flow rate of 1.0 ml/min, approximate retention times of 3.3, 5.1 and 9.1 min were obtained for the internal standard, mesal-amine and NAS, respectively. Mesalamine and NAS concentrations in plasma and urine were calculated based on the peak height ratios of mesalaminel internal standard or NAS/internal standard for the specimens and using response factors from the daily standard curve. The calibration curves for mesalamine and NAS in plasma were linear (r > 0.992) over the ranges 0.025 - 1 and 0.05 - 2.5 ,ug/ml, respectively, and mean (± SD) recoveries of mesalamine and NAS from plasma were 103.4 ± 2.7% and 92.6 ± 5.2%, respectively. The mean (± SD) interassay precision of the plasma method for mesalamine over the two studies was 6.5 ± 2.2% and the accuracy was 100.0 ± 3.0%. For NAS the interassay precision of the plasma method over the two studies was 5.7 ± 2.1% and the accuracy was 97.6 ± 6.4%. For mesalamine and NAS method sensitivities were 0.025 and 0.05 ,ug/ml, respectively, in human plasma. The calibration curves for mesalamine and NAS in urine were linear (r > 0.993) over the ranges 1 - 20 and 10 - 200 ,ug/ml, respectively, and the mean (± SD) recoveries for mesalamine and NAS from urine were 90.4 ± 2.3% and 89.0 ± 2.0%, respectively. The mean (± SD) interassay precision of the urine method over the two studies for mesalamine was 6.1 ± 2.0% and the accuracy was 99.9 ± 4.4%. For NAS
443 Downloaded from imr.sagepub.com by guest on August 4, 2016
A.B. Corey, O.M. Rose. J.D. Conklin over the two studies the mean (± SO) inprecision of the urine method was 5.1 ± 1.9% and the accuracy was 96.9 ± 5.8%. The method sensitivities for mesalamine and NAS in human urine were 1 and 10 Jlg/ml, respectively. ~assay
Pharmacokinetic analysis Based on the variable release of drug that has been reported for dosage forms similar to enteric-coated mesalamine,S.IO-12 which is probably due to inter- and intrasubject variations in gastro-intestinal conditions, it was anticipated that complete pharmacokinetic characterizations might not be possible with the limited number of specimens that could be collected in these crossover studies. All calculations were performed using in-house programs. Maximum plasma drug concentration «;...), time to CItlllX• (tmax) , minimum plasma drug concentration (Cmin) and time until onset of measurable plasma drug concentration (t delay) were reported as observed. Area under the plasma drug concentration - time curve (AUC) from zero time to the last collection time was calculated by the trapezoidal rule, and AUe from zero to infinite time (AUC 0 _..) was calculated by extrapolation using the elimination rate constant. The plasma terminal half-life of drug elimination was calculated on the basis of the slope of the terminal loglinear portion of the plasma drug concentration - time profile, using only plasma concentrations greater than method sensitivity; a proprietary least-squares regression program was used for these calculations. Urine drug dose recovery (DR) was calculated by standard methods, which included an adjustment for the difference in molecular weight difference between mesalamine and NAS in the calculation of the urine DR for NAS. It has been reported that following administration of mesalamine, mesalamine and NAS detected in human plasma and urine by most analytical methods accounted
for all drug and known metabolites," and it has also been shown that there was very little biliary excretion of mesalamine and NAS,14.ls therefore the total amount of mesalamine absorbed could be determined by combining urine mesalamine and NAS DRs. Using an adjustment for the molecular weight difference between mesalamine and NAS, plasma mesalamine and NAS AUCs were combined to reflect total systemic availability of mesalamine.
Statistical analysis For both studies, comparisons of parameters were made using analysis of variance procedures; all analyses were two-sided and used a significance level of 0.05. In addition, for study 1 confidence intervals between treatment means were calculated at the 0.025 level using Sidak's method, to assure that the overall probability of a type I error in these comparisons was no more than 0.05. It should be noted that there was a large degree of intersubject variation, and as a result, only low statistical power to detect a 20% difference in the parameters could be attained, despite the relatively large subject populations used for each study. This situation was not entirely unanticipated and it was intended to determine meaningful differences and similarities in product performance on both a mean and individual subject basis. RESULTS
Study 1 The mean plasma mesalamine concentration - time profiles obtainedfollowing single oral 800 mg mesalamine doses as two enteric-coated tablets and as four 500 mg sulphasalazine tablets are shown in Fig. I and the corresponding plasma NAS concentration - time profiles are illustrated in Fig. 2. Mesalamine and NAS pharmacokinetic results for the two products are summarized in Table I, and combined plasma mesal-amine and NAS AUCs, as well as urine mesalamine and NAS DRs, are
444 Downloaded from imr.sagepub.com by guest on August 4, 2016
Bioavailability of enteric-eoated mesalamine
1.5
- t - - Enteric-coated masalamine - - >+- -
o
Sulphasalazine
20
40
60
Time (h)
Fig. 1. Mean (± SD) plasma mesaIamine concentrations in healthy volunteers after administration of a single oral 800 mg mesalamine dose as two enteric-coated tablets or as four 500 mg sulphasalazine tablets.
1.5
- t - - Enteric-coated masalamine -
-)Eo -
Sulphasalazine
1.0
~ -=
