Psychopharmacology © Springer-Verlag 1992
Psychopharmacology (1992) 106: S 40-S 42
Mini-Paper Influence of moclobemide on ibuprofen-induced faecal blood loss T.W. Giintert ~, M. Schmitt l, J. Dingemanse 1, and J.H.G. Jonkman 2 1 Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd, CH-4002 Basel, Switzerland 2 Pharma Bio-Research Int. B.V., NL-9471 GP Zuidlaren, The Netherlands
Abstract. In a p h a r m a c o l o g i c a l screen on d r u g - d r u g interactions performed in l a b o r a t o r y animals m o c l o b e m i d e potentiated at high doses the antiphlogistic/anti-inflamm a t o r y activity o f ibuprofen. Therefore, a study was u n d e r t a k e n to determine in healthy volunteers the faecal blood loss induced by multiple doses o f ibuprofen (600 m g t.i.d.) in presence and absence o f steady-state concentrations o f c o n c o m i t a n t l y administered moclobemide (150 m g t.i.d.). The results show that multiple doses o f m o c l o b e m i d e do n o t change faecal b l o o d loss induced by ibuprofen. F u r t h e r m o r e , no clinically relevant p h a r m a c o k i n e t i c interaction between the two drugs studied was detected.
Key words: M o c l o b e m i d e - I b u p r o f e n - Interaction Pharmacokinetics - P h a r m a c o d y n a m i c s
D u r i n g a screen for d r u g - d r u g interactions in the rat, an enhanced antiphlogistic/anti-inflammatory activity o f ibuprofen was seen when high doses o f m o c l o b e m i d e were co-administered. The present study was therefore designed to establish if, at therapeutic doses, there is also an interaction between m o c l o b e m i d e and ibuprofen in m a n which would affect the safety o f treated patients. I b u p r o f e n - i n d u c e d faecal b l o o d loss in healthy volunteers was taken as the p r i m a r y p a r a m e t e r to investigate such an interaction.
Materials and methods Study synopsis. Twenty-four healthy volunteers were included in this double-blind, placebo-controlled trial. The subjects were randomly assigned to two groups and received either moclohemide 150 mg t.i.d. (group A, n= 12) or placebo (group B, n = 12) during the first 2 weeks (days 1-14). On days 8-14 (when moclobemide concentrations were at steady state in group A), the volunteers in Offprint requests to: T.W. Giintert
both groups received ibuprofen tablets (600 mg t.i.d.). During the third week (days 15-21), all the subjects received placebo. To allow monitoring of faecal blood loss (FBL), all volunteers underwent slChromium labelling of erythrocytes (Mollison and Veall 1955) 3 days before the start of drug administration. The volunteers collected all faeces during the entire study period. Quantification of FBL was achieved based on radioactivity measurements in the collected faeces and in blood samples, which were obtained for this purpose every second day. Blood samples were also collected for comparison of the pharmacokinetics of ibuprofen (profiles on days 8 and 14) in the two groups of volunteers and for the evaluation of moclobemide concentrations (profiles on days 7, 14) in both the absence and presence of ibuprofen. The two drugs were determined by specific and sensitive chromatographic procedures (HPLC) combined with UV detection. Data analysis. For statistical analysis, the FBL observations in a particular week were averaged in every individual over the first 3 and the last 4 days. This facilitated comparisons between weeks and treatment groups by analyses of variance (ANOVA, a=0.05). The pharmacokinetics of ibuprofen and moclobemide were both determined using model-independent data analysis. Hence, the parameters AUC0z (area under plasma concentration-time curve in a dosing interval), Cmax (maximum concentration after a dose), Tm,x (time of Cm,~), tl/2 (half-life of terminal disposition phase), VI3/F (distribution volume confounded with bioavailability) and fu (protein-unbound drug fraction in serum; ibuprofen only) could be compared between observation days and/or between treatment groups (ANOVA).
Results and discussion N o difference in the F B L was observed between our two study g r o u p s in any o f the study periods (Table 1, Fig. 1), indicating that m o c l o b e m i d e had no significant additional effect on bleeding induced by ibuprofen. The pattern o f blood loss over the three study periods was similar in the two groups: faecal b l o o d loss increased f r o m the baseline values in week 1 (group A 0.41 _+0.15 m l / d a y ; g r o u p B 0.45 _+0.18 ml/day) to statistically significantly higher values u p o n ibuprofen co-administration on days 8-10 ( 0 . 7 8 + 0 . 5 9 m l / d a y ; 0.80_+0.58 ml/day) a n d days 11-14 ( 1 . 4 9 + 0 . 9 5 m l / d a y ; 1.28_+0.62 ml/day). A t the
$41
Table 1. Average ( ± SD) ibuprofen-induced faecal blood loss (ml/ day) in moclobemide and placebo groups
Table 2. Pharmacokinetic parameters of ibuprofen in moclobemide and placebo groups (day 14)
Days of the study
Parameter
Moclobemide group (Group A)
Placebo group (Group B)
Cm.x T~ax
38 ± 1.8 ± 158 ± 1.94 ± 11 ± 0.30%_+
42 _ 1.1 ± 139 ± 1.76 ± 9.9 _ 0.31%_+
Moclobemide group (Group A)
Placebo group (Group B)
0,40-t-0.23 0.40-t-0.21
0.55+0.53 0.37±0.13
0.78 ± 0 . 5 9 a 1.49 ± 0.95 b
0.80±0.58" 1.28 &0.62 b
0.91 ___0.52~ 0.74 + 0.30 b, c
0.92 ± 0.47" 0.68 ± 0.48 b,
Week 1 1-2-3 4-5-6-7
Week 2 8-9-10 11 - 1 2 - 1 3 -
14
A U C o8h tl/2 V[jF
fu
10 mg/1 1.4 h 24 h - mg/l 0.52h 4.9 1 0.06 %
9 rag/1 0.92 h 15 h - rag/1 0.30h 1.1 1 0.07 %
Week 3 1 5 - 1 6 - 17 18-19-20-21
a Statistically higher than days 1-3 of week 1 b Statistically higher than days 4-7 of week 1 ° Statistically lower than days 4-7 of week 2
end of the third week (days 18-21), the blood loss had declined but the values remained slightly, though statistically significantly higher than the baseline. An analysis of the power in the statistical comparisons revealed that a moclobemide-ibuprofen interaction leading to a 130 % or higher increase of the ibuprofen-induced faecal blood loss would have been detected in our study with a probability of 80% (~=0.05). The mean daily blood loss in our subjects during the run-in period (week t) - 0 . 4 3 4-0.08 ml/day was in good agreement with baseline data reported from other studies in healthy volunteers (Thompson and Anderson 1970; Porro et al. 1977; Salom et al. 1984). Furthermore, the
ibuprofen-induced bleeding in our study was comparable to that found by other investigators (1.2-2 ml/day). Pharmacokinetic findings on ibuprofen (Table 2) also failed to reveal statistically significant differences between the two treatment groups. This was true for parameters describing the absorption (Cmax~T~.. AUC) and for parameters describing the disposition (V~/F, fu, tuz ). Moclobemide plasma concentration-time profiles on day 7 (before ibuprofen administration) and day 14 (during concomitant ibuprofen administration) were almost superimposable, indicating the absence of an influence of ibuprofen on moclobemide steady-state pharmacokinetics. No significant change occurred in rate and extent of moclobemide absorption (day 7: Cmax=1954+317ng/ml, Tm,x=1___0.7 h; day 14: Cm,x= 1858+_297 ng/ml, Tmax= 1.2_+0.8 h); areas under the curves remained unchanged and no difference was observed in clearance values (C1/F) between day 7 (21.7-t-11.9 l/h) and day 14 (21.1_+ 12.5 l/h). Moclobe-
3.0-
2.5-
2.0:>, q~
E 1.5d
r,n
LL
1.0-
0.5-
12 Days
13 14
ii
15 16 17 18
Fig. 1. Faecal blood loss after ibuprofen ad-
ministration (600 mg t.i.d.) combined with moclobemide (150 mg t.i.d.) or placebo. [] M o c l o b e mide group; • placebo group 19 20 21
$42 mide elimination half-lives decreased slightly though statistically significantly from 2.69-t-0.91 h (day 7) to 2.55_+0.86 h (day 14).
Conclusions Concomitant administration of ibuprofen and moclobemide to healthy volunteers did not result in a statistically significant interaction, either on the p h a r m a c o d y n a m i c (faecal blood loss) or the pharmacokinetic level.
References PL Mollison, N Veall (1955) The use of the isotope 51Cr as a label for red cells. Br J Haematol 1: 62-74 Porro B, Corvi G, Fucella LM, Goldaniga GC, Valzelli G (1977) Gastrointestinal blood loss during administration of indoprofen, aspirin and ibuprofen. J Int Med Res 5:155-160 Salom IR, Jacob G, Jallad N, Perdoma C, Mullane J, Weidler D, (1984) Gastrointestinal microbleeding associated with the use of etodolac, ibuprofen, indomethacin and naproxen in normal males. Clin J Pharmacol 24:240-246 Thompson M, Anderson M (1970) Studies of gastrointestinal blood loss during ibuprofen therapy. Rheum Phys Med 10:104-107
Psychopharmacology (1992) 106: S 40-S 42
Mini-Paper Influence of moclobemide on ibuprofen-induced faecal blood loss T.W. Giintert ~, M. Schmitt l, J. Dingemanse 1, and J.H.G. Jonkman 2 1 Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd, CH-4002 Basel, Switzerland 2 Pharma Bio-Research Int. B.V., NL-9471 GP Zuidlaren, The Netherlands
Abstract. In a p h a r m a c o l o g i c a l screen on d r u g - d r u g interactions performed in l a b o r a t o r y animals m o c l o b e m i d e potentiated at high doses the antiphlogistic/anti-inflamm a t o r y activity o f ibuprofen. Therefore, a study was u n d e r t a k e n to determine in healthy volunteers the faecal blood loss induced by multiple doses o f ibuprofen (600 m g t.i.d.) in presence and absence o f steady-state concentrations o f c o n c o m i t a n t l y administered moclobemide (150 m g t.i.d.). The results show that multiple doses o f m o c l o b e m i d e do n o t change faecal b l o o d loss induced by ibuprofen. F u r t h e r m o r e , no clinically relevant p h a r m a c o k i n e t i c interaction between the two drugs studied was detected.
Key words: M o c l o b e m i d e - I b u p r o f e n - Interaction Pharmacokinetics - P h a r m a c o d y n a m i c s
D u r i n g a screen for d r u g - d r u g interactions in the rat, an enhanced antiphlogistic/anti-inflammatory activity o f ibuprofen was seen when high doses o f m o c l o b e m i d e were co-administered. The present study was therefore designed to establish if, at therapeutic doses, there is also an interaction between m o c l o b e m i d e and ibuprofen in m a n which would affect the safety o f treated patients. I b u p r o f e n - i n d u c e d faecal b l o o d loss in healthy volunteers was taken as the p r i m a r y p a r a m e t e r to investigate such an interaction.
Materials and methods Study synopsis. Twenty-four healthy volunteers were included in this double-blind, placebo-controlled trial. The subjects were randomly assigned to two groups and received either moclohemide 150 mg t.i.d. (group A, n= 12) or placebo (group B, n = 12) during the first 2 weeks (days 1-14). On days 8-14 (when moclobemide concentrations were at steady state in group A), the volunteers in Offprint requests to: T.W. Giintert
both groups received ibuprofen tablets (600 mg t.i.d.). During the third week (days 15-21), all the subjects received placebo. To allow monitoring of faecal blood loss (FBL), all volunteers underwent slChromium labelling of erythrocytes (Mollison and Veall 1955) 3 days before the start of drug administration. The volunteers collected all faeces during the entire study period. Quantification of FBL was achieved based on radioactivity measurements in the collected faeces and in blood samples, which were obtained for this purpose every second day. Blood samples were also collected for comparison of the pharmacokinetics of ibuprofen (profiles on days 8 and 14) in the two groups of volunteers and for the evaluation of moclobemide concentrations (profiles on days 7, 14) in both the absence and presence of ibuprofen. The two drugs were determined by specific and sensitive chromatographic procedures (HPLC) combined with UV detection. Data analysis. For statistical analysis, the FBL observations in a particular week were averaged in every individual over the first 3 and the last 4 days. This facilitated comparisons between weeks and treatment groups by analyses of variance (ANOVA, a=0.05). The pharmacokinetics of ibuprofen and moclobemide were both determined using model-independent data analysis. Hence, the parameters AUC0z (area under plasma concentration-time curve in a dosing interval), Cmax (maximum concentration after a dose), Tm,x (time of Cm,~), tl/2 (half-life of terminal disposition phase), VI3/F (distribution volume confounded with bioavailability) and fu (protein-unbound drug fraction in serum; ibuprofen only) could be compared between observation days and/or between treatment groups (ANOVA).
Results and discussion N o difference in the F B L was observed between our two study g r o u p s in any o f the study periods (Table 1, Fig. 1), indicating that m o c l o b e m i d e had no significant additional effect on bleeding induced by ibuprofen. The pattern o f blood loss over the three study periods was similar in the two groups: faecal b l o o d loss increased f r o m the baseline values in week 1 (group A 0.41 _+0.15 m l / d a y ; g r o u p B 0.45 _+0.18 ml/day) to statistically significantly higher values u p o n ibuprofen co-administration on days 8-10 ( 0 . 7 8 + 0 . 5 9 m l / d a y ; 0.80_+0.58 ml/day) a n d days 11-14 ( 1 . 4 9 + 0 . 9 5 m l / d a y ; 1.28_+0.62 ml/day). A t the
$41
Table 1. Average ( ± SD) ibuprofen-induced faecal blood loss (ml/ day) in moclobemide and placebo groups
Table 2. Pharmacokinetic parameters of ibuprofen in moclobemide and placebo groups (day 14)
Days of the study
Parameter
Moclobemide group (Group A)
Placebo group (Group B)
Cm.x T~ax
38 ± 1.8 ± 158 ± 1.94 ± 11 ± 0.30%_+
42 _ 1.1 ± 139 ± 1.76 ± 9.9 _ 0.31%_+
Moclobemide group (Group A)
Placebo group (Group B)
0,40-t-0.23 0.40-t-0.21
0.55+0.53 0.37±0.13
0.78 ± 0 . 5 9 a 1.49 ± 0.95 b
0.80±0.58" 1.28 &0.62 b
0.91 ___0.52~ 0.74 + 0.30 b, c
0.92 ± 0.47" 0.68 ± 0.48 b,
Week 1 1-2-3 4-5-6-7
Week 2 8-9-10 11 - 1 2 - 1 3 -
14
A U C o8h tl/2 V[jF
fu
10 mg/1 1.4 h 24 h - mg/l 0.52h 4.9 1 0.06 %
9 rag/1 0.92 h 15 h - rag/1 0.30h 1.1 1 0.07 %
Week 3 1 5 - 1 6 - 17 18-19-20-21
a Statistically higher than days 1-3 of week 1 b Statistically higher than days 4-7 of week 1 ° Statistically lower than days 4-7 of week 2
end of the third week (days 18-21), the blood loss had declined but the values remained slightly, though statistically significantly higher than the baseline. An analysis of the power in the statistical comparisons revealed that a moclobemide-ibuprofen interaction leading to a 130 % or higher increase of the ibuprofen-induced faecal blood loss would have been detected in our study with a probability of 80% (~=0.05). The mean daily blood loss in our subjects during the run-in period (week t) - 0 . 4 3 4-0.08 ml/day was in good agreement with baseline data reported from other studies in healthy volunteers (Thompson and Anderson 1970; Porro et al. 1977; Salom et al. 1984). Furthermore, the
ibuprofen-induced bleeding in our study was comparable to that found by other investigators (1.2-2 ml/day). Pharmacokinetic findings on ibuprofen (Table 2) also failed to reveal statistically significant differences between the two treatment groups. This was true for parameters describing the absorption (Cmax~T~.. AUC) and for parameters describing the disposition (V~/F, fu, tuz ). Moclobemide plasma concentration-time profiles on day 7 (before ibuprofen administration) and day 14 (during concomitant ibuprofen administration) were almost superimposable, indicating the absence of an influence of ibuprofen on moclobemide steady-state pharmacokinetics. No significant change occurred in rate and extent of moclobemide absorption (day 7: Cmax=1954+317ng/ml, Tm,x=1___0.7 h; day 14: Cm,x= 1858+_297 ng/ml, Tmax= 1.2_+0.8 h); areas under the curves remained unchanged and no difference was observed in clearance values (C1/F) between day 7 (21.7-t-11.9 l/h) and day 14 (21.1_+ 12.5 l/h). Moclobe-
3.0-
2.5-
2.0:>, q~
E 1.5d
r,n
LL
1.0-
0.5-
12 Days
13 14
ii
15 16 17 18
Fig. 1. Faecal blood loss after ibuprofen ad-
ministration (600 mg t.i.d.) combined with moclobemide (150 mg t.i.d.) or placebo. [] M o c l o b e mide group; • placebo group 19 20 21
$42 mide elimination half-lives decreased slightly though statistically significantly from 2.69-t-0.91 h (day 7) to 2.55_+0.86 h (day 14).
Conclusions Concomitant administration of ibuprofen and moclobemide to healthy volunteers did not result in a statistically significant interaction, either on the p h a r m a c o d y n a m i c (faecal blood loss) or the pharmacokinetic level.
References PL Mollison, N Veall (1955) The use of the isotope 51Cr as a label for red cells. Br J Haematol 1: 62-74 Porro B, Corvi G, Fucella LM, Goldaniga GC, Valzelli G (1977) Gastrointestinal blood loss during administration of indoprofen, aspirin and ibuprofen. J Int Med Res 5:155-160 Salom IR, Jacob G, Jallad N, Perdoma C, Mullane J, Weidler D, (1984) Gastrointestinal microbleeding associated with the use of etodolac, ibuprofen, indomethacin and naproxen in normal males. Clin J Pharmacol 24:240-246 Thompson M, Anderson M (1970) Studies of gastrointestinal blood loss during ibuprofen therapy. Rheum Phys Med 10:104-107
