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Effect of food on the pharmacokinetics of the active metabolite of the prodrug repirinast
Effect of Food on the Pharmacokinetics of the Active Metabolite of the Prodrug Repirinast HANS G. SCHAEFER*',DIETERBEERMA"*, ROLF HORSTMANN*,MANFRED WARGENAU~, B R I G I ~A.E HEIBEL', AND JOCHEN KUHLMANN* Received September 18, 1991, from *Ba er AG, Pharma Research Center, Institute of Clinical Pharmacology, P.O. Box 101709, 5600 Wuppettal 1, *BayerAG, Pharma lesearch Center, Institute of Biometry, P.O. Box 101709, 5600 Wuppettal 1, and the 'Institute Clinical Pharmacology, Prof. Lucker GmbH, 6718 Grunstadt, Germany. Accepted for publication June 15, 1992. Abstract 0 The effect of food on the pharmacokinetics of the active metabolite of the new antiasthmatic drug repirinast was investigated in two different studies after oral administration of 300 mg of repirinast. In each study, 12 healthy volunteers received the repirinast dose under fasting or fed conditions in a crossover manner. In one study, a high-fat meal (American breakfast) was used and in another study, a low-fat, high-carbohydrate meal (continental breakfast) was used. Concentrations of the active metabolite in plasma and urine were determined by reversed-phase high-performance liquid chromatography with UV detection. After administration of repirinast with a low-fat and a high-fat meal, the relative bioavailability of the active metabolite increased by factors of 1.9 and 2.4, respectively,as expressed by area under the curve of concentration versus time from 0 to 12 h. The amount excreted into urine doubled after drug administration with both types of food and accounted for -8% of the dose under fasting conditions and -16% of the dose under fed conditions. Maximum concentrations in plasma were different between the two studies: mean maximum concentrations in plasma increased by factors of 1.7 and 3.2 after administration of drug with a low-fat (drug intake immediately after breakfast) and a high-fat breakfast (drug intake just before breakfast),respectively,compared with fasting conditions.
Repirinast is a new, synthetic, disodium cromoglycate-like antiallergic agent'-3 for oral administration in humans. Since 1987,the drug has been marketed for the treatment of asthma in Japan. Repirinast is a prodrug,4 and in plasma, only the active metabolite (deesterified repirinast) and not the parent compound was detected after oral, single-dose administration (seestructure). The enteral absorption of the metabolite itself is poor in the dog.67 Therefore, deesterification may occur during passage through the gut wall andor liver or in blood. This process may be influenced by food, because food will change gastric emptying, gastrointestinal motility, enzyme activity in the gastrointestinal tract, and splanchnic blood fl0w.B-10 Repirinast itself is practically insoluble in water (11.2 mg/L), but solubility increases -100 times in peanut oil. Therefore, solubility of repirinast in the chyme may increase and, as a consequence, the in vivo release of drug from the dosage form may be influenced by food ingestion. In addition, solubility and absorption of some lipid-solubledrugs 0 11
<
C- 0-CH, CH2 CH cH3 CH3 0 4
REPlRlNAST
ACTIVE METABOLITE
OO22-3~9/93/0100-0107$02.50/0 0 1993, American Pharmaceutical Association
is enhanced by bile salts released in response to food ingestion.8 To examine a possible food effect on the pharmacokinetics of the active metabolite after oral administration of repirinast, two different studies were performed in healthy volunteers, with low- and high-fat meals.
Experimental Section Design-Both studies were performed with the same experimental design; that is, a randomized, non-blind, crossover study with single dose administration of 300 mg of repirinast and a wash-out period of 1 week. Study protocols were approved by the Institutional Review Board of the Institute of Clinical Pharmacology Bobenheim and the Ethics Committee of the Board of Physicians, Nordrhein. The time period between the studies was 6 months. Due to the time lagbetween the studies and the fact that studies were performed at different study sites, drug intake relative to food differed in both studies. Under fasting conditions, all volunteers received 300 mg of repirinast (2 x 150-mgtablets) after an overnight fast and, under fed conditions, the same dose was given either immediately followinga low-fatbreakfast or immediately before the high-fat breakfast. Tablets were taken together with 100 mL of tap water. Both groups remained sitting for 30 min until the breakfast was finished. For all volunteers, standardized lunch and dinner were served 5 and 10 h after drug intake, respectively. Food Composition-The high-carbohydrate, low-fat breakfast (continental breakfast; study 1) consisted of two buns, one slice of rye bread with jam, ham, and cottage cheese, whereas the high-fat breakfast (American breakfast; study 2) included two fried eggs, two strips of bacon, and two slices of toast with butter and jam. Caffeinefree coffee was served in both studies. Subjects-Twelve healthy male volunteers participated in each study. The volunteers gave their written informed consent after full explanation of the trial procedure. The mean ages and weights of the volunteers in studies 1and 2 were 28.3 -t 4.4years and 74.4 2 8.1 kg and 27.8 f 5.1 years and 73.3 f 9.0kg,respectively. Prior to the drug administrations, the subjects underwent a medical evaluation that included a physical examination, evaluation of vital signs, lung function, 12-lead electrocardiogram, and laboratory tests (hematology, clinical chemistry, urinalysis). Study Drug-Repirinast tablets (150 mg, Batch no. 523291)were supplied by Bayer AG, Leverkusen, Germany. In vitro dissolution tests (US paddle 50 rpm, 0.1 M HC1+ 0.25% sodium dodecylsulfate, 900 mL) showed that 90% of the dose was released within 15 min. Specimen Collection-Blood samples (5 mL) for the analysis of the active metabolite were obtained through an indwelling catheter just before administration and 0.5,0.75,1,1.5,2,2.5,3,4,6,8,12,24,32, 48, and 72 h after drug administration. The blood samples were immediately centrifuged, and the plasma was separated and divided into 1-mL aliquots. To each 1-mL sample, 100 pL of 1 M HC1 was added and thoroughly mixed, and the mixture was stored in glass tubes at -20 "C until assayed. Urine was collected from 0-12,12-24, 2 4 4 8 , and 48-72 hours after drug intake. Aliquots were stored at -20 "C until analysis. High-Performance Liquid Chromatography (HPLC) Assay of the Active Metaboliteplasma and urine samples were analyzed for the metabolite by reversed-phase HPLC with LJV detection.11CaliJournal of Pharmaceutical Sciences I 107 Vol. 82, No. 1, January 1993
as the metabolite) under fasting conditions and - 16% of the dose under fed conditions were found in urine (Table I). Mean CL, values ranged from 250 to 500 mllmin. The C, was reached a short time after repirinast intake after completion of the continental breakfast, whereas repirinast administration at the beginning of the American breakfast resulted in earlier attainment of C,, compared with the fasting conditions. In several cases, concentrations of drug in plasma after administration under fasting conditions could be followed over a longer time period (up to 32 h after administration) than after administration under nonfasting conditions. This resulted in calculation of a longer terminal t,, for the fasting condition.
bration curves were linear from 0.01 to 2 mg/L (correlation coefficient = 0.998). Intra- and interday variabilities were
Discussion
Ingestion of food is well known to change the bioavailability of a number of drugs. This effect of food is due to either the pharmacokinetics of the drug moiety itself andlor t o changes in the in vivo drug release from the dosage form (influence on disintegration and dissolution).l~-17In this study, the systemic availability of the active metabolite is significantly increased after administration of the prodrug repirinast under fed conditions. The differencesin the study designs with regard to type of food and time of drug administration relative to food had only minor influences on bioavailability of the metabolite as expressed by AUC(0-12) and Ae,,, whereas the effect of the differences on C , is more pronounced. The values is about twice as high when increase in mean C, repirinast is administered at the beginning of a high-fat breakfast as compared with administration after completion of a low-fat breakfast. The high-fat breakfast might increase the solubility of repirinast in the chyme more rapidly, resultResults ing in a steeper increase of concentrations in plasma compared with the low-fat breakfast. Administration at the end Mean plasma concentration-time curves [expressed as of the meal leads to prolonged gastric residence, which geometric mean; geometric standard deviation (SD)] of the provides more time for drug dissolution compared with fastactive metabolite after administration of repirinast under ing conditions. The change in the t,, may reflect the fasting and fed conditions are illustrated in Figure 1A different times of drug administration with respect to inges(continental breakfast) and 1B (American breakfast), respection of the two meals. Administration just at the beginning of tively. The pharmacokinetic parameters from both studies the high-fat breakfast resulted in a decrease oft,, compared are summarized in Table I. Drug intake together with food with the control, whereas administration of repirinast after markedly increased concentrations of the metabolite in completion of a low-fat breakfast resulted in slightly proplasma (Figures 1 and 2). The mean values of 1.9 (90% longed t, values. The fact that metabolite concentrations in confidence interval, 1.63-2.26) and 2.4 (90% confidence inplasma were detectable over a longer time period after terval, 1.87-3.08) for the ratio AUC(O-12)breakfasJAUC(Oadministration of repirinast to volunteers in the fasted state 12)fashddemonstrate a significant increase in AUC(0-12) by compared with administration together with food indicates these factors after repirinast intake with low and high fat incomplete absorption in the upper part of the gastrointestibreakfasts, respectively (Tables I and 11). nal tract and, therefore, ongoing absorption in the lower Mean C, values increased by factors of 1.7 (90% confiparts. Thus, terminal tlI2values for both conditions were not dence interval, 1.35-2.02) and 3.2 (90% confidence interval, comparable because, for fasted conditions, the terminal tl12 2.4-4.2) for the low- and high-fat breakfasts, respectively was calculated from beyond 6 h (in some volunteers up to 72 (Table 11).The Ae,, doubled (statistically significant change) h) and under fed conditions, concentrations in plasma from 4 after drug administration with both types of food (Table 11). to 8 h were included in the calculation of terminal tl12. After repirinast administration, -8% of the dose (calculated Table I-Pharmacokinetic Parameters of the Active Metabolite of Repirinasta
AUC(O-l2), mg * h/L AUC(0-in), mg h/L
.
C,,,
mg/L
h ti121 h C k , rnUmin Ae,,, % of dose Lax7
a Values
American Breakfast
Continental Breakfast
Parameter
Fasted
Fed
Fasted
Fed
0.61 (1.31) 0.74 (1.40) 0.27 (1.35) 0.73 (1.41) 12.7 (3.84) 303 (2.26) 7.76 (2.33)
1.17 (1.36) 1.16 (1.37) 0.44 (1.25) 1.07 (1.32) 2.46 (2.61) 497 (1.27) 15.4 (1.54)
0.93 (1.45) 1 . 1 1 (1.56) 0.35 (1.65) 1.03 (1.85) 15.4 (2.00) 248 (1.39) 8.75 (1.50)
2.23 (1.47) 2.38 (1.42) 1.13 (1.47) 0.68 (1.51) 7.11 (2.90) 277 (1.28) 17.6 (1 52)
expressed as geometric mean (SD); oral dose of 300 mg of repirinast.
108 / Journal of Pharmaceutical Sciences Vol. 82, No. 1, January 1993
0.60
p
A
-
5'5
-
0.50--
u
.-
4.5 5'0
0.40.-
1
CONTINENTAL BREAKFAST
M R I C A N BREAKFAST
1
I
a .
0 .L u
5
0.30-
0
0.20-
i
2
0.10-2 I
L
0.00
Time [h]
FASTING
2.0
-
1.6 1.4 1.2 1.0 -
FED
CONTINENTAL BREAKFAST
FASTING
AMERICAN BREAKFAST h
1.8
g 0
h
_..
5
E
Time [h]
Figure 1-Mean metabolite plasma concentration-time profiles after oral administration of 300 mg of repirinast under fasting conditions (0) or with (A) continental or (B) American breakfasts (0). Table ii-Fed/Fasted
Ratios of AUC(O-12), C,. Continental Breakfast
Parameter
Fed/ 90% Fasted Confidence Ratioa Interval
AUC(O-12), mg * h/L C m a , mg/L Ae,,, mg a Values
and Ae... American Breakfast Fed/ Fasted Ratio'
90% Confidence interval
1.92 (1.47) 1.63-2.26 2.40 (1 5 4 ) 1.874.08 1.65 (1.47) 1.35-2.02 3.17 (1.61) 2.42-4.16 2.07 (2.19) 1 . 3 r ~ 3 . 1 82.01 (1.56) 1.58-2.55
expressed as geometric mean (geometric SD).
With the data generated in this study it cannot be concluded whether the observed food effect is due to the dosage form or the chemical entity itself. However, results from in vitro dissolution tests showed that -90% of the dose was released within 15 min. Therefore, it might be more likely that increased solubility of repirinast in the chyme is the major mechanism of the observed effect.
References and Notes 1. Miyamoto, A.;Takahaski, S.; Shida, T.; Kabe, J.; Makino, S.Med. Consult. New Remed. 1986,23, 251-276. 2. Takahashi, K.; Arai, Y.; Kadowaki, S.; Shono, T.; Yuki, S. Pharmucometrics (OVOYakuri) 1986. 32, 233-249. 3. Takishima, T.; Mue; S.; Ohmi, T.; T G u g i , R.; Takahashi, K. Jpn. J. Clin. Exp. Med. 1986, 63, 2723-2733.
j
0.8
:
0.4
-
0.2
-
0.6
0.0
FED
'
FASTING
FED
Figure 2-Individual (A) AUC(0-12) and (8), ,C both continental and American breakfasts.
FASTING
FED
values for studies with
4. Yamada, N.; Suzuki, K.; Kadowaki, S.; Tabahashi, K.; Mizogami, S. Jpn. J. Pharmucol. 1988,46(Suppl.), 62 P (Abstract 0-49). 5. Esumi, Y.; Jin, Y.; Uohama, K.; Kashiwazaki, K.; Yohoshima, T. Clin. Rep. 1986,20, 925-940. 6. Ekado, G.; Kami, Y.; Okada, Y.; Katami, Y.; Takaichi, M.; Ohtsuki, T.; Yokojima, T.; Uchide M.; Morinaka, Y. Clin. Rep. 1986,20,941-955. 7. Iwamoto, A.; Ichide, M.; Takamatsu, Y.; Kondo, H.; Onuma, K. Clin. Rep. 1986,20, 95G964. 8. Welling, P. G. J. Pharm. Biopharm. 1977, 5, 291-234. 9. Roberts, J.; Turner, N. Pharmacol. Ther. 1988,37, 111-149. 10. Kuhlmann, J. Med. Mo. Pharm. 1978,1, 289-302. 11. Beermann, D.; Schaefer, H. G.; Wargenau, M.; Heibel, B.; Sturm, Y.; Kuhlmann, J . Eur. J. Clin. Pharmucol. 1992,42, 307-312. 12. Gibaldi, M.; Perrier, D. Pharmucokinetics, 2nd ed.; Marcel Dekker: New York, 1982; pp 409417. 13. Hauschke, D.; Steinijans, V. W.; Diletti, E. Znt. J. Clin. Pharmacol. Ther. Toxicol. 1990,28, 72-78. 14. Pabst, G.; Jaeger, H. Eur. J. Clin. Pharrnucol. 1990, 38, 5-10. 15. Holazo, A. A.; Pinili, E. E.; de Grazia, F. T.; Patel, I. H. Pharm. Res. 1990, 7, 777-779. 16. Jonkman, J. H. G. Chronobiol. Znt. 1987,4, 449-458. 17. Overdiek, H. W.; Merkus, F. W. Clin. Pharmucol. Ther. 1986,40, 531-536.
Journal of Pharmaceutical Sciences I 109 Vol. 82, No. 1, January 1993
Repirinast is a new, synthetic, disodium cromoglycate-like antiallergic agent'-3 for oral administration in humans. Since 1987,the drug has been marketed for the treatment of asthma in Japan. Repirinast is a prodrug,4 and in plasma, only the active metabolite (deesterified repirinast) and not the parent compound was detected after oral, single-dose administration (seestructure). The enteral absorption of the metabolite itself is poor in the dog.67 Therefore, deesterification may occur during passage through the gut wall andor liver or in blood. This process may be influenced by food, because food will change gastric emptying, gastrointestinal motility, enzyme activity in the gastrointestinal tract, and splanchnic blood fl0w.B-10 Repirinast itself is practically insoluble in water (11.2 mg/L), but solubility increases -100 times in peanut oil. Therefore, solubility of repirinast in the chyme may increase and, as a consequence, the in vivo release of drug from the dosage form may be influenced by food ingestion. In addition, solubility and absorption of some lipid-solubledrugs 0 11
<
C- 0-CH, CH2 CH cH3 CH3 0 4
REPlRlNAST
ACTIVE METABOLITE
OO22-3~9/93/0100-0107$02.50/0 0 1993, American Pharmaceutical Association
is enhanced by bile salts released in response to food ingestion.8 To examine a possible food effect on the pharmacokinetics of the active metabolite after oral administration of repirinast, two different studies were performed in healthy volunteers, with low- and high-fat meals.
Experimental Section Design-Both studies were performed with the same experimental design; that is, a randomized, non-blind, crossover study with single dose administration of 300 mg of repirinast and a wash-out period of 1 week. Study protocols were approved by the Institutional Review Board of the Institute of Clinical Pharmacology Bobenheim and the Ethics Committee of the Board of Physicians, Nordrhein. The time period between the studies was 6 months. Due to the time lagbetween the studies and the fact that studies were performed at different study sites, drug intake relative to food differed in both studies. Under fasting conditions, all volunteers received 300 mg of repirinast (2 x 150-mgtablets) after an overnight fast and, under fed conditions, the same dose was given either immediately followinga low-fatbreakfast or immediately before the high-fat breakfast. Tablets were taken together with 100 mL of tap water. Both groups remained sitting for 30 min until the breakfast was finished. For all volunteers, standardized lunch and dinner were served 5 and 10 h after drug intake, respectively. Food Composition-The high-carbohydrate, low-fat breakfast (continental breakfast; study 1) consisted of two buns, one slice of rye bread with jam, ham, and cottage cheese, whereas the high-fat breakfast (American breakfast; study 2) included two fried eggs, two strips of bacon, and two slices of toast with butter and jam. Caffeinefree coffee was served in both studies. Subjects-Twelve healthy male volunteers participated in each study. The volunteers gave their written informed consent after full explanation of the trial procedure. The mean ages and weights of the volunteers in studies 1and 2 were 28.3 -t 4.4years and 74.4 2 8.1 kg and 27.8 f 5.1 years and 73.3 f 9.0kg,respectively. Prior to the drug administrations, the subjects underwent a medical evaluation that included a physical examination, evaluation of vital signs, lung function, 12-lead electrocardiogram, and laboratory tests (hematology, clinical chemistry, urinalysis). Study Drug-Repirinast tablets (150 mg, Batch no. 523291)were supplied by Bayer AG, Leverkusen, Germany. In vitro dissolution tests (US paddle 50 rpm, 0.1 M HC1+ 0.25% sodium dodecylsulfate, 900 mL) showed that 90% of the dose was released within 15 min. Specimen Collection-Blood samples (5 mL) for the analysis of the active metabolite were obtained through an indwelling catheter just before administration and 0.5,0.75,1,1.5,2,2.5,3,4,6,8,12,24,32, 48, and 72 h after drug administration. The blood samples were immediately centrifuged, and the plasma was separated and divided into 1-mL aliquots. To each 1-mL sample, 100 pL of 1 M HC1 was added and thoroughly mixed, and the mixture was stored in glass tubes at -20 "C until assayed. Urine was collected from 0-12,12-24, 2 4 4 8 , and 48-72 hours after drug intake. Aliquots were stored at -20 "C until analysis. High-Performance Liquid Chromatography (HPLC) Assay of the Active Metaboliteplasma and urine samples were analyzed for the metabolite by reversed-phase HPLC with LJV detection.11CaliJournal of Pharmaceutical Sciences I 107 Vol. 82, No. 1, January 1993
as the metabolite) under fasting conditions and - 16% of the dose under fed conditions were found in urine (Table I). Mean CL, values ranged from 250 to 500 mllmin. The C, was reached a short time after repirinast intake after completion of the continental breakfast, whereas repirinast administration at the beginning of the American breakfast resulted in earlier attainment of C,, compared with the fasting conditions. In several cases, concentrations of drug in plasma after administration under fasting conditions could be followed over a longer time period (up to 32 h after administration) than after administration under nonfasting conditions. This resulted in calculation of a longer terminal t,, for the fasting condition.
bration curves were linear from 0.01 to 2 mg/L (correlation coefficient = 0.998). Intra- and interday variabilities were
Discussion
Ingestion of food is well known to change the bioavailability of a number of drugs. This effect of food is due to either the pharmacokinetics of the drug moiety itself andlor t o changes in the in vivo drug release from the dosage form (influence on disintegration and dissolution).l~-17In this study, the systemic availability of the active metabolite is significantly increased after administration of the prodrug repirinast under fed conditions. The differencesin the study designs with regard to type of food and time of drug administration relative to food had only minor influences on bioavailability of the metabolite as expressed by AUC(0-12) and Ae,,, whereas the effect of the differences on C , is more pronounced. The values is about twice as high when increase in mean C, repirinast is administered at the beginning of a high-fat breakfast as compared with administration after completion of a low-fat breakfast. The high-fat breakfast might increase the solubility of repirinast in the chyme more rapidly, resultResults ing in a steeper increase of concentrations in plasma compared with the low-fat breakfast. Administration at the end Mean plasma concentration-time curves [expressed as of the meal leads to prolonged gastric residence, which geometric mean; geometric standard deviation (SD)] of the provides more time for drug dissolution compared with fastactive metabolite after administration of repirinast under ing conditions. The change in the t,, may reflect the fasting and fed conditions are illustrated in Figure 1A different times of drug administration with respect to inges(continental breakfast) and 1B (American breakfast), respection of the two meals. Administration just at the beginning of tively. The pharmacokinetic parameters from both studies the high-fat breakfast resulted in a decrease oft,, compared are summarized in Table I. Drug intake together with food with the control, whereas administration of repirinast after markedly increased concentrations of the metabolite in completion of a low-fat breakfast resulted in slightly proplasma (Figures 1 and 2). The mean values of 1.9 (90% longed t, values. The fact that metabolite concentrations in confidence interval, 1.63-2.26) and 2.4 (90% confidence inplasma were detectable over a longer time period after terval, 1.87-3.08) for the ratio AUC(O-12)breakfasJAUC(Oadministration of repirinast to volunteers in the fasted state 12)fashddemonstrate a significant increase in AUC(0-12) by compared with administration together with food indicates these factors after repirinast intake with low and high fat incomplete absorption in the upper part of the gastrointestibreakfasts, respectively (Tables I and 11). nal tract and, therefore, ongoing absorption in the lower Mean C, values increased by factors of 1.7 (90% confiparts. Thus, terminal tlI2values for both conditions were not dence interval, 1.35-2.02) and 3.2 (90% confidence interval, comparable because, for fasted conditions, the terminal tl12 2.4-4.2) for the low- and high-fat breakfasts, respectively was calculated from beyond 6 h (in some volunteers up to 72 (Table 11).The Ae,, doubled (statistically significant change) h) and under fed conditions, concentrations in plasma from 4 after drug administration with both types of food (Table 11). to 8 h were included in the calculation of terminal tl12. After repirinast administration, -8% of the dose (calculated Table I-Pharmacokinetic Parameters of the Active Metabolite of Repirinasta
AUC(O-l2), mg * h/L AUC(0-in), mg h/L
.
C,,,
mg/L
h ti121 h C k , rnUmin Ae,,, % of dose Lax7
a Values
American Breakfast
Continental Breakfast
Parameter
Fasted
Fed
Fasted
Fed
0.61 (1.31) 0.74 (1.40) 0.27 (1.35) 0.73 (1.41) 12.7 (3.84) 303 (2.26) 7.76 (2.33)
1.17 (1.36) 1.16 (1.37) 0.44 (1.25) 1.07 (1.32) 2.46 (2.61) 497 (1.27) 15.4 (1.54)
0.93 (1.45) 1 . 1 1 (1.56) 0.35 (1.65) 1.03 (1.85) 15.4 (2.00) 248 (1.39) 8.75 (1.50)
2.23 (1.47) 2.38 (1.42) 1.13 (1.47) 0.68 (1.51) 7.11 (2.90) 277 (1.28) 17.6 (1 52)
expressed as geometric mean (SD); oral dose of 300 mg of repirinast.
108 / Journal of Pharmaceutical Sciences Vol. 82, No. 1, January 1993
0.60
p
A
-
5'5
-
0.50--
u
.-
4.5 5'0
0.40.-
1
CONTINENTAL BREAKFAST
M R I C A N BREAKFAST
1
I
a .
0 .L u
5
0.30-
0
0.20-
i
2
0.10-2 I
L
0.00
Time [h]
FASTING
2.0
-
1.6 1.4 1.2 1.0 -
FED
CONTINENTAL BREAKFAST
FASTING
AMERICAN BREAKFAST h
1.8
g 0
h
_..
5
E
Time [h]
Figure 1-Mean metabolite plasma concentration-time profiles after oral administration of 300 mg of repirinast under fasting conditions (0) or with (A) continental or (B) American breakfasts (0). Table ii-Fed/Fasted
Ratios of AUC(O-12), C,. Continental Breakfast
Parameter
Fed/ 90% Fasted Confidence Ratioa Interval
AUC(O-12), mg * h/L C m a , mg/L Ae,,, mg a Values
and Ae... American Breakfast Fed/ Fasted Ratio'
90% Confidence interval
1.92 (1.47) 1.63-2.26 2.40 (1 5 4 ) 1.874.08 1.65 (1.47) 1.35-2.02 3.17 (1.61) 2.42-4.16 2.07 (2.19) 1 . 3 r ~ 3 . 1 82.01 (1.56) 1.58-2.55
expressed as geometric mean (geometric SD).
With the data generated in this study it cannot be concluded whether the observed food effect is due to the dosage form or the chemical entity itself. However, results from in vitro dissolution tests showed that -90% of the dose was released within 15 min. Therefore, it might be more likely that increased solubility of repirinast in the chyme is the major mechanism of the observed effect.
References and Notes 1. Miyamoto, A.;Takahaski, S.; Shida, T.; Kabe, J.; Makino, S.Med. Consult. New Remed. 1986,23, 251-276. 2. Takahashi, K.; Arai, Y.; Kadowaki, S.; Shono, T.; Yuki, S. Pharmucometrics (OVOYakuri) 1986. 32, 233-249. 3. Takishima, T.; Mue; S.; Ohmi, T.; T G u g i , R.; Takahashi, K. Jpn. J. Clin. Exp. Med. 1986, 63, 2723-2733.
j
0.8
:
0.4
-
0.2
-
0.6
0.0
FED
'
FASTING
FED
Figure 2-Individual (A) AUC(0-12) and (8), ,C both continental and American breakfasts.
FASTING
FED
values for studies with
4. Yamada, N.; Suzuki, K.; Kadowaki, S.; Tabahashi, K.; Mizogami, S. Jpn. J. Pharmucol. 1988,46(Suppl.), 62 P (Abstract 0-49). 5. Esumi, Y.; Jin, Y.; Uohama, K.; Kashiwazaki, K.; Yohoshima, T. Clin. Rep. 1986,20, 925-940. 6. Ekado, G.; Kami, Y.; Okada, Y.; Katami, Y.; Takaichi, M.; Ohtsuki, T.; Yokojima, T.; Uchide M.; Morinaka, Y. Clin. Rep. 1986,20,941-955. 7. Iwamoto, A.; Ichide, M.; Takamatsu, Y.; Kondo, H.; Onuma, K. Clin. Rep. 1986,20, 95G964. 8. Welling, P. G. J. Pharm. Biopharm. 1977, 5, 291-234. 9. Roberts, J.; Turner, N. Pharmacol. Ther. 1988,37, 111-149. 10. Kuhlmann, J. Med. Mo. Pharm. 1978,1, 289-302. 11. Beermann, D.; Schaefer, H. G.; Wargenau, M.; Heibel, B.; Sturm, Y.; Kuhlmann, J . Eur. J. Clin. Pharmucol. 1992,42, 307-312. 12. Gibaldi, M.; Perrier, D. Pharmucokinetics, 2nd ed.; Marcel Dekker: New York, 1982; pp 409417. 13. Hauschke, D.; Steinijans, V. W.; Diletti, E. Znt. J. Clin. Pharmacol. Ther. Toxicol. 1990,28, 72-78. 14. Pabst, G.; Jaeger, H. Eur. J. Clin. Pharrnucol. 1990, 38, 5-10. 15. Holazo, A. A.; Pinili, E. E.; de Grazia, F. T.; Patel, I. H. Pharm. Res. 1990, 7, 777-779. 16. Jonkman, J. H. G. Chronobiol. Znt. 1987,4, 449-458. 17. Overdiek, H. W.; Merkus, F. W. Clin. Pharmucol. Ther. 1986,40, 531-536.
Journal of Pharmaceutical Sciences I 109 Vol. 82, No. 1, January 1993