Absorption and excretion of tolmetin in man Tolmetin, a nonsteroidal anti-inflammatory drug, is rapidly absorbed (10 to 20 min) and rapidly excreted (Ph. "" 60 min) and shows a linear dose-plasma level response in the therapeutic dose range. Tolmetin does not affect its own metabolism on chronic administration. Tolmetin is displaced, in vitro, from plasma proteins by salicylic acid. This effect is reflected in minor changes in plasma levels and pharmacokinetic parameters when aspirin and tolmetin are coadministered.
William A. Cressman, Ph.D., G. Forrest Wortham, M.D., and Janis Plostnieks, Ph.D. Fort Washington, Pa.
Departments of Biochemistry and Clinical Investigation, McNeil Laboratories, Inc.
Tolmetin* is a new arylpyrrole acetic acid anti-inflammatory agent that has shown significant anti-inflammatory activity and greater safety than presently available antiarthritic drugs. 1, 2, 3, 5-12, 14-17,20 Its chemical structure is shown in Fig. 1. Clinical trials with tolmetin are presently being conducted. In order to develop information on parameters that might affect the plasma levels of tolmetin in human subjects, several pharmacokinetic studies were conducted to evaluate: (1) the relationship of the dose of tolmetin to its plasma levels; (2) the relative bioavailability of the two tablet dosage forms in use clinically; (3) the effect of repeated administration of tolmetin on its plasma levels; (4) the effect of repeated concomitant administration of tolmetin and aspirin on the plasma levels of tolmetin; and (5) the in vitro plasma protein bindin& characteristics of tolmetin and salicylic acid. Received for publication May 8, 1975. Accepted for publication Oct. 17. 1975. Reprint requests to: William A. Cressman. Ph.D .• McNeil Laboratories. Inc .. Camp Hill Road. Fort Washington. Pa. 19034. *Tolmetin is available from McNeil Labs. Inc .. as Tolectin tolmetin sodium tablets.
224
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tained at the 3 dose levels.
Experimental
Normal healthy male subjects were used in all studies. The subjects were free of any recognizable medical or surgical disease and had not received any drugs for a period of at least two weeks prior to the study. Subjects with a history of peptic ulcer or other gastrointestinal abnormality were excluded from the study. On days plasma was collected, the subjects fasted overnight (at least 12 hr) prior to drug administration. No foods or liquids, except water, were consumed for at least 3 hr after dosing, when a standard light meal was eaten. At least 4 hr elapsed after the standard meal before normal unrestricted diet was resumed. All doses of tolmetin were calculated as the free acid but were administered as the sodium salt dihydrate. For the solution doses, the drug
Tolmetin
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Fig. 2. Mean plasma levels (± 1 SE) of tolmetin in 6 human subjects administered 200 mg ( 0), 600 mg (.), and 800 mg (_) of tolmetin as an oral solution in a crossover design. was dissolved in 150 ml of water prior to administration. Tablet doses were taken with 150 ml of water. Heparinized blood was collected pre-dose (0 hr) and at appropriate time intervals after dosing. The plasma was separated by centrifugation and stored frozen until analysis. The samples were analyzed4 using a gas chromatographic (aspirin study) or spectrophotometric technique (all other studies). Clinical studies
Dose-response study. Six subjects received, according to a Latin-square design, 200, 600, or 800 mg of tolmetin orally in solution. Heparinized blood was collected pre-dose and at 10, 20, 40, 60, and 90 min and 2, 3, 4, 5, 7, 10, and 24 hr post-dosing. Bioavailability study. Eighteen subjects received, according to a Latin-square design, 400 mg of tolmetin as 100-mg tablets, 200-mg
tablets, or a solution. Heparinized blood was collected pre-dose and at 10, 20, 40, 60, and 90 min and 2, 3, 4, 5, 7, 10, and 24 hr postdosing. Chronic administration study. Twelve subjects received the following dosage regimen of tolmetin. On day 1, after an overnight fast, the 12 subjects received 400 mg of tolmetin as an aqueous solution. Heparinized blood was collected pre-dose at 20, 40, 60, and 90 min and 2, 3, 4,5,7, 10, and 24 hr after dosing. On days 3 to 17 each subject received 300 mg of tolmetin (3 X 100 mg tablets) 4 times daily at approximately 8:00 A.M., 12:00 noon, 4:00 P.M., and 8:00 P.M. On day 18, after an overnight fast, the subjects received 400 mg of tolmetin as an aqueous solution and heparinized blood was collected as on day 1. Chronic administration with asptrm. Eleven subjects received the following dosage regimen of tolmetin and tolmetin-aspirin. On
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Fig. 3. Correlation of administered dose with amount absorbed, corrected area under the plasma level curve, uncorrected area under the plasma level curve, peak plasma level, and plasma elimination half-life. Range bars represent I SD.
day 1, after an overnight fast, the 11 subjects received 400 mg of to1metin as an aqueous solution. Heparinized blood was collected predose and at 20, 40, 60, and 90 min and 2, 3, 4, 5, 7, 10, and 24 hr post-dosing. On days 3 to 17 each subject received 300 mg of to1metin (3 x 100 mg tablets) and 975 mg of aspirin (3 x 325 mg tablets) 4 times daily at approximately 8:00 A.M., 12:00 noon, 4:00 P.M., and 8:00 P.M. On day 18, after an overnight fast, the subjects received 400 mg of tolmetin as an aqueous solution and 975 mg of aspirin (3 x 325 mg tablets). Heparinized blood was collected as on day 1.
Protein binding The binding of tolmetin and salicylic acid to plasma proteins was determined in vitro using eqUilibrium dialysis, at room temperature. Heparinized plasma samples were seeded with radioactive tolmetin or radioactive salicylic acid as required. Six ml of a 0.125 M,
pH 7.4 phosphate buffer containing the to1metin and/or the salicylic acid was added to 24 ml of plasma. Aliquots of this solution were used for the equilibrium dialysis determination of plasma protein binding using the 0.125 M buffer as the external solution. The radioactivity in each phase was determined and the per cent of bound drug calculated.
Results
Dose-response study. The mean plasma levels (± SE) of tolmetin obtained at the 3 dose levels are shown in Fig. 2. For convenience, all plasma data in this report have been corrected to a 150-lb subject weight. This correction assumes a linear relationship between plasma levels and subject weight. The correlation of administered dose with amount absorbed, corrected area under the plasma level curve, uncorrected area under the plasma level curve, peak plasma level, and plasma elimination half-life are illustrated in
Tolmetin
Volume 19 Number 2
227
Table I. Summary of the linear regression analyses of the data for 6 subjects given 200 mg, 600 mg, and 800 mg doses of tolmetin Ho(slope = 0)
Ho (straight line)
Milligrams No at p ,,;; 0.05 absorbed Area vs dose Noatp,,;; 0.05
Yes at p ,,;; 0.05 Yes at p ,,;; 0.05
Corrected area vs dose Peak height
Noatp,,;; 0.05
Yes at p ,,;; 0.05
Noatp,,;; 0.05
Half-life
Noatp,,;; 0.05
Intercept (95% confidence limits)
Slope (95% confidence limits)
Correlation coefficient
+58 to + 114) (+2 -478 (+693 to -1,649) +6.7 (-0.3 to + 13.7)
+0.94 (+0.73 to + 1.15) +12.1 (+7.4 to + 16.8) +0.107 (+0.078to +0.135)
0.91
Yes at p ,,;; 0.05
+2.9 (-5.8 to + 11.6)
+0.110 (+0.075to +0.115)
0.86
Yes at p ,,;; 0.05
+42.3 (+35.0 to +49.6)
+0.031 (+0.002 to +0.060)
0.54
0.81 0.91
Ho: null hypothesis.
Table 11. Plasma half-lives (minutes) of tolmetin in human subjects who received 200, 600, or 800 mg of tolmetin as an oral solution Subject
200-mg dose
600-mgdose
800-mg dose
1 2 3 4 5 6
57 48 41 42 33 68
55 60 62 58 52 82
51 82 60 57 58 90
Mean ± SD
48 ± 13
62 ± 11
66 ± 16
0.26
0.17
0.24
CV*
* Coefficient of variation.
Fig. 3. The linear regression analyses of these data, which are summarized in Table I, provide statistical confirmation that there is a linear relationship between dose and amount of drug absorbed. The method of Wagner and Nelson 18 was used to calculate from the plasma level data the amount of tolmetin absorbed. The values were calculated relative to the 800-mg dose, i.e., absorption of the 800-mg dose equals, by definition, 100% absorption. The half-lives used in these calculations are given in Table 11. These Wagner and Nelson data transformations were calculated to provide a relative ratio of the extent of the absorption of tolmetin. The corrected areas under the plasma level curve were obtained by correcting the individual area values for the half-life of tolmetin observed in that subject with that treatment. This method of correction was described by
Wagner and Darniano 19 and assumes that the extent of absorption is better indicated by (O.693/half-life) x area than by area alone. Bioavailability study. The mean plasma levels of tolmetin obtained with the solution and the 100-mg and 200-mg tablets are shown in Fig. 4. The plasma levels were not statistically different at any time points. At all postabsorption time points, the statistics were capable of detecting a 20% to 25% difference between treatments. * The areas under the curves for the 100-mg tablet, 200-mg tablet, and
* Based on the experimental data. the stated per cent difference in means is the minimum difference that could be detected by analy. sis of variance at the p ,;;; 0.05 level. Any means differing by more than the stated percentage would be statistically significantly different. This percentage provides an indication of the ability (sensitivity) of the experiment to adequately differentiate the relative bioavailabilities of the dosage forms studied.
228
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Cressman, Wortham, and Plostnieks
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William A. Cressman, Ph.D., G. Forrest Wortham, M.D., and Janis Plostnieks, Ph.D. Fort Washington, Pa.
Departments of Biochemistry and Clinical Investigation, McNeil Laboratories, Inc.
Tolmetin* is a new arylpyrrole acetic acid anti-inflammatory agent that has shown significant anti-inflammatory activity and greater safety than presently available antiarthritic drugs. 1, 2, 3, 5-12, 14-17,20 Its chemical structure is shown in Fig. 1. Clinical trials with tolmetin are presently being conducted. In order to develop information on parameters that might affect the plasma levels of tolmetin in human subjects, several pharmacokinetic studies were conducted to evaluate: (1) the relationship of the dose of tolmetin to its plasma levels; (2) the relative bioavailability of the two tablet dosage forms in use clinically; (3) the effect of repeated administration of tolmetin on its plasma levels; (4) the effect of repeated concomitant administration of tolmetin and aspirin on the plasma levels of tolmetin; and (5) the in vitro plasma protein bindin& characteristics of tolmetin and salicylic acid. Received for publication May 8, 1975. Accepted for publication Oct. 17. 1975. Reprint requests to: William A. Cressman. Ph.D .• McNeil Laboratories. Inc .. Camp Hill Road. Fort Washington. Pa. 19034. *Tolmetin is available from McNeil Labs. Inc .. as Tolectin tolmetin sodium tablets.
224
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CH,
CH, -
COOH
I
CHa Fig. 1. Mean plasma levels (±SE) of tolmetin ob-
tained at the 3 dose levels.
Experimental
Normal healthy male subjects were used in all studies. The subjects were free of any recognizable medical or surgical disease and had not received any drugs for a period of at least two weeks prior to the study. Subjects with a history of peptic ulcer or other gastrointestinal abnormality were excluded from the study. On days plasma was collected, the subjects fasted overnight (at least 12 hr) prior to drug administration. No foods or liquids, except water, were consumed for at least 3 hr after dosing, when a standard light meal was eaten. At least 4 hr elapsed after the standard meal before normal unrestricted diet was resumed. All doses of tolmetin were calculated as the free acid but were administered as the sodium salt dihydrate. For the solution doses, the drug
Tolmetin
Volume 19 Number 2
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Fig. 2. Mean plasma levels (± 1 SE) of tolmetin in 6 human subjects administered 200 mg ( 0), 600 mg (.), and 800 mg (_) of tolmetin as an oral solution in a crossover design. was dissolved in 150 ml of water prior to administration. Tablet doses were taken with 150 ml of water. Heparinized blood was collected pre-dose (0 hr) and at appropriate time intervals after dosing. The plasma was separated by centrifugation and stored frozen until analysis. The samples were analyzed4 using a gas chromatographic (aspirin study) or spectrophotometric technique (all other studies). Clinical studies
Dose-response study. Six subjects received, according to a Latin-square design, 200, 600, or 800 mg of tolmetin orally in solution. Heparinized blood was collected pre-dose and at 10, 20, 40, 60, and 90 min and 2, 3, 4, 5, 7, 10, and 24 hr post-dosing. Bioavailability study. Eighteen subjects received, according to a Latin-square design, 400 mg of tolmetin as 100-mg tablets, 200-mg
tablets, or a solution. Heparinized blood was collected pre-dose and at 10, 20, 40, 60, and 90 min and 2, 3, 4, 5, 7, 10, and 24 hr postdosing. Chronic administration study. Twelve subjects received the following dosage regimen of tolmetin. On day 1, after an overnight fast, the 12 subjects received 400 mg of tolmetin as an aqueous solution. Heparinized blood was collected pre-dose at 20, 40, 60, and 90 min and 2, 3, 4,5,7, 10, and 24 hr after dosing. On days 3 to 17 each subject received 300 mg of tolmetin (3 X 100 mg tablets) 4 times daily at approximately 8:00 A.M., 12:00 noon, 4:00 P.M., and 8:00 P.M. On day 18, after an overnight fast, the subjects received 400 mg of tolmetin as an aqueous solution and heparinized blood was collected as on day 1. Chronic administration with asptrm. Eleven subjects received the following dosage regimen of tolmetin and tolmetin-aspirin. On
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Fig. 3. Correlation of administered dose with amount absorbed, corrected area under the plasma level curve, uncorrected area under the plasma level curve, peak plasma level, and plasma elimination half-life. Range bars represent I SD.
day 1, after an overnight fast, the 11 subjects received 400 mg of to1metin as an aqueous solution. Heparinized blood was collected predose and at 20, 40, 60, and 90 min and 2, 3, 4, 5, 7, 10, and 24 hr post-dosing. On days 3 to 17 each subject received 300 mg of to1metin (3 x 100 mg tablets) and 975 mg of aspirin (3 x 325 mg tablets) 4 times daily at approximately 8:00 A.M., 12:00 noon, 4:00 P.M., and 8:00 P.M. On day 18, after an overnight fast, the subjects received 400 mg of tolmetin as an aqueous solution and 975 mg of aspirin (3 x 325 mg tablets). Heparinized blood was collected as on day 1.
Protein binding The binding of tolmetin and salicylic acid to plasma proteins was determined in vitro using eqUilibrium dialysis, at room temperature. Heparinized plasma samples were seeded with radioactive tolmetin or radioactive salicylic acid as required. Six ml of a 0.125 M,
pH 7.4 phosphate buffer containing the to1metin and/or the salicylic acid was added to 24 ml of plasma. Aliquots of this solution were used for the equilibrium dialysis determination of plasma protein binding using the 0.125 M buffer as the external solution. The radioactivity in each phase was determined and the per cent of bound drug calculated.
Results
Dose-response study. The mean plasma levels (± SE) of tolmetin obtained at the 3 dose levels are shown in Fig. 2. For convenience, all plasma data in this report have been corrected to a 150-lb subject weight. This correction assumes a linear relationship between plasma levels and subject weight. The correlation of administered dose with amount absorbed, corrected area under the plasma level curve, uncorrected area under the plasma level curve, peak plasma level, and plasma elimination half-life are illustrated in
Tolmetin
Volume 19 Number 2
227
Table I. Summary of the linear regression analyses of the data for 6 subjects given 200 mg, 600 mg, and 800 mg doses of tolmetin Ho(slope = 0)
Ho (straight line)
Milligrams No at p ,,;; 0.05 absorbed Area vs dose Noatp,,;; 0.05
Yes at p ,,;; 0.05 Yes at p ,,;; 0.05
Corrected area vs dose Peak height
Noatp,,;; 0.05
Yes at p ,,;; 0.05
Noatp,,;; 0.05
Half-life
Noatp,,;; 0.05
Intercept (95% confidence limits)
Slope (95% confidence limits)
Correlation coefficient
+58 to + 114) (+2 -478 (+693 to -1,649) +6.7 (-0.3 to + 13.7)
+0.94 (+0.73 to + 1.15) +12.1 (+7.4 to + 16.8) +0.107 (+0.078to +0.135)
0.91
Yes at p ,,;; 0.05
+2.9 (-5.8 to + 11.6)
+0.110 (+0.075to +0.115)
0.86
Yes at p ,,;; 0.05
+42.3 (+35.0 to +49.6)
+0.031 (+0.002 to +0.060)
0.54
0.81 0.91
Ho: null hypothesis.
Table 11. Plasma half-lives (minutes) of tolmetin in human subjects who received 200, 600, or 800 mg of tolmetin as an oral solution Subject
200-mg dose
600-mgdose
800-mg dose
1 2 3 4 5 6
57 48 41 42 33 68
55 60 62 58 52 82
51 82 60 57 58 90
Mean ± SD
48 ± 13
62 ± 11
66 ± 16
0.26
0.17
0.24
CV*
* Coefficient of variation.
Fig. 3. The linear regression analyses of these data, which are summarized in Table I, provide statistical confirmation that there is a linear relationship between dose and amount of drug absorbed. The method of Wagner and Nelson 18 was used to calculate from the plasma level data the amount of tolmetin absorbed. The values were calculated relative to the 800-mg dose, i.e., absorption of the 800-mg dose equals, by definition, 100% absorption. The half-lives used in these calculations are given in Table 11. These Wagner and Nelson data transformations were calculated to provide a relative ratio of the extent of the absorption of tolmetin. The corrected areas under the plasma level curve were obtained by correcting the individual area values for the half-life of tolmetin observed in that subject with that treatment. This method of correction was described by
Wagner and Darniano 19 and assumes that the extent of absorption is better indicated by (O.693/half-life) x area than by area alone. Bioavailability study. The mean plasma levels of tolmetin obtained with the solution and the 100-mg and 200-mg tablets are shown in Fig. 4. The plasma levels were not statistically different at any time points. At all postabsorption time points, the statistics were capable of detecting a 20% to 25% difference between treatments. * The areas under the curves for the 100-mg tablet, 200-mg tablet, and
* Based on the experimental data. the stated per cent difference in means is the minimum difference that could be detected by analy. sis of variance at the p ,;;; 0.05 level. Any means differing by more than the stated percentage would be statistically significantly different. This percentage provides an indication of the ability (sensitivity) of the experiment to adequately differentiate the relative bioavailabilities of the dosage forms studied.
228
Clinical Pharmacology and Therapeutics
Cressman, Wortham, and Plostnieks
20
::::" ] 0
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