BIOPHARMACEUTICS & DRUG DISPOSITION, VOL. 12, 435-445 (1991)
COMPARATIVE BIOAVAILABILITY OF TWO FLURBIPROFEN PRODUCTS: STEREOSPECIFIC VERSUS CONVENTIONAL APPROACH FAKHREDDIN JAMALI*, DAVID S. COLLINStll, BRIAN W. BERRY*, SUSAN MOLDERS, RICHARD CHEUNGS, KATE McCOLLt AND HELEN CHEUNGS
*Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Ehonton, Alberta t Victoria Upjohn Research Clinic, Victoria Hospital, London, Ontario $The Upjohn Company of Canada, Don Mills, Ontario 5Department of Epidemiology & Biostatistics, the University of Western Ontario, London, Ontario, Canada
ABSTRACT In this randomized, crossover study comparing the bioavailability of a film-coated (Ansaid) with a sugar-coated (Froben) 100 mg tablets of racemic flurbiprofen in 23 ,t or AUC, using healthy young men, no significant differences were found for C, a nonstereoisomeric assay for flurbiprofen. Minor differences in the appearance of flurbiprofen in serum during the first 30-min post-dosing period were noted, with Ansaid appearing earlier than Froben. These differences likely reflect dissolution rate dissimilarity between the two products. Stereospecific determinations demonstrate a small (7.8 per cent) but significant difference in AUC of the active S-configuration (Froben> Ansaid). No significant differences between Ansaid and Froben were found for t,, or C,,, for the S-flurbiprofen. In bioequivalency studies of chiral drugs, stereospecific approaches provide a more accurate assessment of products. KEY WORDS
Flurbiprofen Bioequivalence Pharmacokinetics Enantiomers Stereospecific Stereoselective
INTRODUCTION Flurbiprofen, S,R-2-(2-fluoro-4-biphenylyl)propionic acid, is an orally effective nonsteroidal antiinflammatory drug (NSAID) with antipyretic and analgesic properties. It is useful in the management of mild to moderately severe pain syndromes and in arthritic conditions. Flurbiprofen is marketed in Canada as film-coated (Ansaid, the Upjohn Company of Canada, Don Mills, Ontario) and sugar-coated (Froben, Organon Canada Ltd, West Hill, Ontario) tablets. A previous study carried out on research lots of Ansaid and Froben 100 mg tablets provided evidence that Ansaid had a significantly shorter,,f than Froben. (D. J. Stalker and S. R. Pollock, personal communication). A difference 11 Present address, 420 East St, N, Sarnia, Ontario, Canada. Correspondenceto: Dr F. Jamali, Faculty of Pharmacy, University of Alberta, Edmonton, Alberta, Canada T6G 2N8 0142-2782/91/060435-11$05.50 0 1991 by John Wiley & Sons, Ltd.
Received 29 August 1990 Revised 12 February 1991
436
F. JAMALI ET A L .
in dissolution rates was identified between 100 mg tablets of Ansaid and Froben (K. S. Channer and J. P. Virgee, personal communication). In addition, the formulation of tablets has been shown to be important in oesophageal transit, with oesophageal clearance of film-coated tablets significantly better than for plain-coated tablets.' The objective of this study was to compare the oral bioavailability of Ansaid 100 mg tablets with that of Froben 100 mg tablets using marketed drug supplies. All of the available flurbiprofen products contain racemic drug. As only the S enantiomer possesses pharmacological activities*it seems essential to examine the bioavailability of the active enantiomer. Thus both stereospecific and nonstereospecific assays were applied to measure flurbiprofen in serum. Only limited data on the pharmacokinetics of flurbiprofen enantiomers are a ~ a i l a b l e .This ~.~ article will provide more information regarding stereoselective disposition kinetics of flurbiprofen in a relatively large sample size.
METHODS Products
Ansaid l00mg tablets (lot W688, The Upjohn Company of Canada, Don Mills, Ontario) and Froben 100mg tablets (lot 03788, Organon Canada Ltd, West Hill, Ontario) were purchased by a hospital pharmacist, independent of the study. Subjects
Twenty-three healthy male volunteers on no other medications participated in the trial. The mean age of the volunteers was 27.2 years (range 18-35 years). The mean weight was 71.8 kg (range 52.5-88.5 kg) and all were within 20 per cent of their ideal body weight according to the Geigy Scientific table^.^ Twelve of 23 volunteers smoked 2-25 cigarettes per day on a routine basis. Each participant was judged to be healthy after a history, physical examination, and laboratory tests (hematology, blood chemistry, and urinalysis). All subjects gave informed consent after a complete explanation of the protocol, approved by the University of Western Ontario's Health Sciences Standing Committee on Human Research. Study design In a two-way crossover, open-label design study with a 6 to 7 day washout period, each subject received one tablet (l00mg) of either brand on each of the two study days. The tablets were ingested with 100ml of tap water after a 10 h overnight fast (one cup of coffee was permitted on rising as long as
FLURBIPROFEN
437
this was taken on both study days). No alcohol-containing beverages were permitted in the 24 h period before a study, on the study day or in the 24 h after a study day. Standardized meals were provided on both study days. Breakfast was provided after the 2 h blood sample had been taken, lunch after the 4 h sample, a snack after the 8 h sample, and dinner after the 12h sample. Subjects were permitted to be ambulatory during the 2-24 h clinic stays. Smoking was permitted. Sampleprocessing and assays Approximately 15ml of venous blood samples for flurbiprofen assay were collected in red top Vacutainer tubes. The serum was harvested after the blood was centrifuged at 3000 rev min-I for 10 min at 4". The serum was divided equally into two portions in untreated plastic vials and glass vials pre-rinsed with 0.5-1.0 ml of 2 M sulphuric acid (to avoid hydrolysis of acyl glucuronides) which were allowed to dry overnight. The serum samples were stored at -20" until analysis. A general nonstereospecificassay6was used with some modifications. Briefly, the sample serum was mixed with internal standard, naproxen lOmg/lOOrnl HPLC-grade acetonitrile. After vortexing and centrifugation, the samples were injected directly into an HPLC. The column was a 10 cm stainless steel (4.6 mm id) 5 pm octadecyl-bonded silica (Partisil 5-ODs-3, Whatman Inc. Clifton, NJ, USA) attached to a 5 cm guard column of the same material with a 10 pm particle size. The mobile phase consisted of acetonitrile: 0.067 M KH2P04: triethylamine (32:68:0-02 v/v) with a flow rate of 1.0ml min-'. Flurbiprofen was detected at 254 nm. For the stereospecific determination, a previously reported HPLC assay was used.7 Treatment of data The two brands were compared on the basis of the maximum serum concentration achieved (C,,,), the time to reach the maximum serum concentration (t,,,), and the area under the 0-24 h serum concentration-time curve (AUC) which was calculated by the trapezoidal rule. A visual inspection of lag time between dosing and first detectable concentrations of flurbiprofen was also done. Stereoselective differences were determined by comparing the enantiomers pharmacokinetic indices. The t1,2of the terminal elimination phase of the serum concentration-time curves was estimated using a regression equation. Statistical significance of the observed differences between the enantiomers concentrations as well as between the pharmacokinetic indices were examined using the paired Student's t-test at a = 0.05.
438
F. JAMALI ET A L .
RESULTS Adverse effects Adverse effects of the medication were minor with subject 21 reporting 1 day of mild dysuria 2 days after dosing with Froben 100 mg. Subject 9 reported a feeling of a 'lump in my throat' persisting approximately 8 h after dosing on both study days. Bioavailability results
Nonstereospeclfic approach. No significant differences were found between the and AUC (Table 1, Figure 1). However, products in terms of their tmaxrCmax, as magnified in Figure 2, serum concentrations of Ansaid was significantly greater than Froben during the initial 30 min post-dosing period.
Table 1. Non-stereoselective bioavailability indices of flurbiprofen Ansaid Subject
Cmax
mg I-'
tmax
h
Froben AUC mg h I-'
Cmax
tmax
mgl-'
h
AUC mg h I-'
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
12.17 10.06 17.5 1 14.02 17.81 13.50 12.97 18.29 11.06 14.4 1 19.28 21.06 19.87 17.60 21.60 18.01 14.34 13.79 16.35 15.86 25.20 2 1.42 18.82
2.00 0.50 1 .oo 1.50 1.75 3.00 2.00 0.25 1.75 2.00 1.25 1.25 1.00 1 .oo 0-75 0.75 0.50 1.50 2-00 1-50 0.25 1 .oo 1.75
66.76 55.52 81.41 67.72 74.57 76.41 70.99 71.15 68.5 1 93.02 80.41 72.35 76.80 77.49 77.82 82.34 52.17 90.99 63.40 74.34 88.89 102.62 185.88
11.49 15.61 12.6 1 13.36 19.14 13.12 16.25 12.4 1 14.92 13.37 15.22 15.88 19.46 14.51 18.63 17.79 16.13 19.40 19.34 14.63 17.60 17.80 20.1 1
4.00 1 .oo 2.00 2.00 1 .oo 2.00 1.50 2.00 1.25 1.75 1.75 1.50 1.75 2.00 2.00 1.25 1.00 1 .oo 0.75 1.00 1 .oo 1 .oo 1.50
72.00 70.38 74.82 64.89 78.25 80.51 83.14 74.76 75.28 86.70 87.48 67.57 75.05 78.04 77.74 81.39 62.21 97.67 66.68 68.06 86.66 98.50 186.69
Mean SD
16.74 3.69
1-32 0.66
80.50 25.12
16.03 2.56
1.57 0.67
82.37 24.10
439
FLURBIPROFEN
2o
1
n
i E
W
Z
0 2 w I-
z
W 0
z
0 0
0
4
a
12
16
20
24
HOURS Figure 1. Mean nonstereospecific serum concentration-time curves of flurbiprofen following oral administration of Ansaid (+) and Froben (0).Error bars represent standard deviation of the means
n
i E W
Z
0
2 IY I-
Z
W
0 Z 0 0
HOURS Figure 2. Two-hour mean nonstereospecific serum concentration-time curves of flurbiprofen following oral administration of Ansaid (+)and Froben @). Error bars represent standard deviation of the means. The differences were significant at 0.25 and 0.50 h
440
F. JAMALI ET AL.
Stereospecijic approach. No significant differences were found between the products with respect to the observed t,,, and C,,, values of either enantiomers (Table 2 and 3, Figure 3). Similarly, the differences in the R enantiomer AUC values of the two products were insignificant. However, AUC of S enantiomer was significantly greater (7.8 per cent) after Froben than Ansaid (Tables 2 and 3). Also, as seen during the nonstereospecific approach, serum concentrations of both enantiomers were significantly greater after Ansaid as compared to Froben during the initial 30-min post-dosing period (Figure 4). With the exception of subject 21, the results of the bioavailability study were very comparable between the two methods when parameters for total (S+R) flurbiprofen were considered for each subject (r2 > 0.90 for Cmxand AUC with slopes of 0.98 and 1.0, respectively). Enantiomers pharmacokinetics Disposition kinetics of flurbiprofen was stereoselective. Following both products, S-flurbiprofen had greater AUC and longer t1,2as compared to its antipode (Tables 2 and 3, Figure 3). No significant amounts of glucuronide-conjugated enantiomers were found in plasma.
DISCUSSION Bioequivalency Based upon the nonstereoSpecific assay the only difference between the two products is a more rapid initial rise in concentration of Ansaid. This may be attributed to a faster dissolution for the film-coated product. The rapid release and absorption of active drug when NSAIDs have been film-coated has also been shown for naproxen.* Nevertheless, this initial difference did not amount to any significant dissimilarities in t,,, or C,,, values of the products. The observed small but significantly greater AUC for S-flurbiprofen (but not for R) following Froben as compared with Ansaid (Tables 2 and 3) is interesting because the S enantiomer has been established to be associated with the majority if not all of the anti-inflammatory activity of nonsteroidal anti-inflammatory drugs with the 2-arylpropionic acid structure.2This observation, although with unknown clinical significance, further emphasizes the importance of the application of proper analytical methods (i.e., stereospecific assays) in the bioequivalency or clinical pharmacology studies.’ The discrepancy between the two approaches is unlikely to stem from a difference in the release or absorption rate of the S-enantiomer. Both release and absorption processes are very likely governed by passive mechanisms hence the observed difference should have been seen for both enantiomers rather then for S-flurbiprofen a10ne.~For ibuprofen, another 2-arylpropionic acid derivative, which undergoes
8.20 1.61
Mean SD
35.13 37.92 42.20 34.32 43.91 45.35 38.81 44-58 3 1-47 46.59 40.74 39.92 40.02 45.48 48.38 44.67 35.84 52.42 40-18 45-06 29.07 61.72 101.20 44.74*7 13.86
1.75 2.00 0.75 1.25 2.00 3.00 2.00 0.25 1.75 2.00 1.50 1.25 1.oo 1.so 1*oo 1.00 0.75 3.00 2.00 1.75 1.oo 2.00 2.00
1.59 0.66
t Significantly different from Froben.
* Significantly greater than R-flurbiprofen.
6.49 6.01 9.38 7.53 9.64 6.44 6.31 9.44 6.13 6.58 7.9 1 9.13 10.27 8.36 10.91 9.31 9.19 7.14 9.60 8.34 5.06 9.83 9.71
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 6.89* 2.65
3.59 6.48 5.87 5.17 4.65 6.30 7.97 7.79 5.82 5.82 8.35 7.70 4.13 5.73 11.18 7.79 6.73 5.97 6.54 5.06 6.93 5.92 16.90 7.91 1.66
5.78 5.89 9.22 7.01 9.6 1 6.41 6.20 9.14 5.08 6.72 8.04 9.5 1 11.05 8.28 9.50 8.87 8.27 6.74 8.97 7.58 4.95 9.79 9-40 1.60 0.65
1.75 2.00 0.75 1.25 2.00 3.00 2.00 0.25 1.75 2.00 1.50 1.25 1.25 1.50 1*oo 1.oo 0.75 3.00 2.00 1.75 1.00 2.00 2.00 38-56 12.94
24.29 3 1.92 40.01 29.25 38.58 39.48 35.32 39.22 24.67 42.99 36.45 37.45 47.09 42.06 40.1 1 37.47 28.64 40.63 32.54 36.05 23.53 48.24 90.84 5.98 2.00
3.01 6.19 5.82 5.87 4.17 5.73 6.03 7.88 5.2 1 5.2 1 7.88 5.54 4.03 5.50 9.63 6.03 6.60 4-95 4.75 4.62 5.41 4.68 12.83 1.04 0-06
1.12 1.02 1.02 1.07 1 .oo 1.oo 1.02 1.03 1.21 0.98 0.98 0.96 0.93 1.01 1.15 1.05 1.1 1 1.06 1.07 1.10 1.02 1.oo 1.03 0.99 0.04
1.oo 1.oo 1.oo 1.oo 1.00
1
.oo
1.oo 1~00 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 0.80 1.oo 1.oo 1.oo 1.oo
1.17 0.1 1
1.45 1.19 1.15 1.17 1.14 1.15 1.10 1.14 1.28 1.08 1.12 1.07 0.85 1.08 1.21 1-19 1.25 1.29 1.23 1.25 1.24 1.28 1-11
Table 2. Pharmacokinetic indices of flurbiprofen enantiomers following administration of single dose of Ansaid
1.15 0.13
1.19 1.05 1.01 0.88 1.11 1.10 1.32 0.99 1.12 1.12 1.06 1.39 1.02 1.04 1.16 1.29 1.02 1.21 1.38 1.09 1.28 1.26 1.32
z
LEl
ti
-
E
6.93 7.42 6.40 6.54 9.23 6.38 8.74 6.03 5.57 6.47 7.39 8.12 8.60 7.20 7.99 8.88 7.19 9.97 10.07 7.94 9.5 9.05 11.09
7.94 1.43
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Mean SD
6.84* 2.84
48.2 1*t 13.89
1.67 0.69
6.30 5.59 6.08 4.71 4.85 6.60 6.54 9.49 6.79 5.10 4.99 6.66 5.63 6.03 6.19 5.97 6.48 6.54 7.79 5.87 5.97 7.97 19.25
57.54 42.29 40.93 35.02 47.69 46,34 42.10 5 1.52 36.42 43.69 43.36 39.69 44.77 44.42 40.88 49.19 39.76 55.81 37.65 43.41 58.17 64.39 103.68
h
4.00 1.50 3.00 2.00 1.25 2.00 1.25 2.00 1.oo 1.75 2.00 1.50 1.25 2.00 2.00 1.25 1.50 1.oo 1.oo 1.00 1.oo 1.50 1.75
t1/2
AUC mg h I-'
S
Tm, h
* Significantly greater than R-flurbiprofen. t Significantly different from Ansaid.
Cmax mgl-l
Subject
1.64 0.62
40.97 12.2 1
6.17 1.97
5.10 5.41 5.87 5.06 5.06 6.93 6.73 8.35 6.08 5.29 4.9 1 5.78 5.33 6.36 5.06 5.25 5.82 5.06 6.54 5.06 4.47 8.25 14.14
39.68 40.1 I 35.34 30.44 43.89 39.14 36.93 44.75 33.69 39.13 39.61 3 1.60 40.04 35.84 34.35 41.59 33.33 41.28 32.90 34.24 51.61 50.30 92.47 4.00 1.50 2.00 1.75 1.25 2.00 1.75 2.00 1.25 1.75 2.00 1 .50 1.50 2.00 2.00 1.25 1.25 1.oo 1.oo 1.oo 1.oo 1.25 1.75
5.76 7.71 6.15 6.71 9.36 6.09 8.57 5.79 5.78 6.63 7.46 7.73 8.55 6.81 8.06 8.29 7.27 9.51 9.97 7.23 10.14 9.13 10.23 7.78 1.43
h
t1/2
AUC mghl-l
Tmax h
Cmax mgl-'
R
1.02 0.15
1.18 0.09
1.45 1.05 1.16 1.15 1.09 1.18 1.14 1.15 1.08 1.12 1.09 1.26 1.12 1.24 1.19 1.18 1.19 1.35 1.14 1.27 1.13 1*28 1.12
1.oo 1.oo 1.50 1.14 1 .oo 1.oo 0.71 1.oo 0.80 1.oo 1.oo 1.oo 0.83 I .oo 1 .oo 1.oo 1.20 1.oo 1.oo 1.oo 1.oo 1.20 1.oo 1.20 0.96 1.04 0.97 0.99 1.05 1.02 1.04 0.96 0.98 0.99 1.05 1.01 1.06 0.99 1.07 0.99 1.05 1.01 1.10 0.94 0.99 I .08 1.02 0.06
AUC
Tmax
Cmax
SIR
Table 3. Pharmacokinetic indices of flurbiprofenenantiomers following administrationof single dose of Froben
1.10 0.13
1.24 1.03 1.04 0.93 0.96 0.95 0.97 1.14 1.12 0.96 1.01 1.15 1.06 0.95 1.22 1.14 1.11 1.29 1.19 1.16 1.34 0.97 1.36
t1/2
P
!-
9
c
5
3
.n
R
443
FLURBIPROFEN
10
8
6
4 A
_J
2
E
2
W
Z
g
1c
t-
4
f
Z w
E
u
Z
0 O
E
L
1
(
p
T
I 0
4
8
12
16
20
24
R to S inversion, it has been proposed that the inversion, and consequently the concentration of the active enantiomer, is influenced by the rate of absorption:'OJ1the slower the rate of absorption the greater the extent of inversion. This could explain greater AUC for the S enantiomer after Froben which has slightly slower rate of absorption than Ansaid (Figures 2 and 3). If so, one expects a corresponding reduction in AUC of the R enantiomer. This, however, may remain undetectable due to the small magnitude of the observed
F. JAMALI ET AL.
0.0
0.5
1 .o
1.5
2.0
HOURS Figure 4. Two-hour mean stereospecific serum concentration-time curves of flurbiprofen following oral administration of Ansaid (S A, R 0 ) and Froben (S A, R 0).Error bars represent standard deviation of the means
differences. Nevertheless, enantiomeric inversion, although a possibility, has not been suggested for flurbiprofen in human^.^ No detectable plasma concentration of S enantiomer was found following ingestion of R enantiomer. This inference, however, is not conclusive as despite undetectable plasma concentrations, approximately 10 per cent of R-ketoprofen doses have been found in urine as S-ketoprofen.I2 Stereoselective pharmacokinetics
In a previous report, pharmacokinetics of flurbiprofen enantiomers have been shown to be stereoselective in six male volunteers with the S enantiomer being predominant in plasma (AUC S/R, 1*13).3The observation reported here is in close agreement with that report. In this study, however, in addition to the stereoselectivity in plasma concentrations, a significant difference was also noted between the enantiomers with respect to their t l l Zwhich is in agreement with a recent report with a sample size of nine.4 Such a difference was not evident in subjects studied previously, due perhaps, to the small sample size. In summary, the mean 7.8 per cent difference in AUC of the pharmacologically active S-flurbiprofen observed between the two products may be of no regulatory or clinical significance. However, the presented data display, for the first time, the importance of using stereospecific assays in bioequivalency studies. From regulatory viewpoints, two bioequivalently different products may be found equivalent when assessed based upon nonstereospecific methods.
FLURBIPROFEN
445
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
K. S. Channer and J. P. Virgee, J. Pharm. Pharmacol., 337, 126 (1985). F. Jamali, Eur. J. Drug Metab. Pharmacokinet., 13, 1 (1988). F. Jamali, B. W. Berry, M. R. Tehrani and A. S. Russell, J. Pharm. Sci.,77,666 (1988). R. E. Small, S. R. Cox and W. J. Adams, J. Clin. Pharmacol., 30,660 (1990). K. Diem and C. Lentner, Ceigy Scientific Tables, Ciba-Geigy Ltd, Basle, Switzerland, 1973. pp. 712. F. Jamali, A. S. Russell, B. W. Berry and C. Lehmann, J. Chromatogr., 310,327 (1984). B. W. Berry and F. Jamali, Phurm. Res., 5 , 123 (1988). K. V. Gaismayer and G. Tausch, Forrschr. Med., 102,601 (1984). F. Jamali, R. Mehvar and F. M. Pasutto, J. Pharm Sci., 78,695 (1989). F. Jamali, N. N. Singh, F. M. Pasutto, R. T. Coutts and A. S. Russell, Pharm. Res., 5, 40 11988). M. T. Borin, S. R. Cox, J. M. Hageman and G. J. Szpunar, Pharm. Res., 10 (suppl.), 159s (1988). F. Jamali, A. S. Russell, R. T. Foster and C. Lemko, J. Pharm. Sci., 79,460 (1990).
. ,
COMPARATIVE BIOAVAILABILITY OF TWO FLURBIPROFEN PRODUCTS: STEREOSPECIFIC VERSUS CONVENTIONAL APPROACH FAKHREDDIN JAMALI*, DAVID S. COLLINStll, BRIAN W. BERRY*, SUSAN MOLDERS, RICHARD CHEUNGS, KATE McCOLLt AND HELEN CHEUNGS
*Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Ehonton, Alberta t Victoria Upjohn Research Clinic, Victoria Hospital, London, Ontario $The Upjohn Company of Canada, Don Mills, Ontario 5Department of Epidemiology & Biostatistics, the University of Western Ontario, London, Ontario, Canada
ABSTRACT In this randomized, crossover study comparing the bioavailability of a film-coated (Ansaid) with a sugar-coated (Froben) 100 mg tablets of racemic flurbiprofen in 23 ,t or AUC, using healthy young men, no significant differences were found for C, a nonstereoisomeric assay for flurbiprofen. Minor differences in the appearance of flurbiprofen in serum during the first 30-min post-dosing period were noted, with Ansaid appearing earlier than Froben. These differences likely reflect dissolution rate dissimilarity between the two products. Stereospecific determinations demonstrate a small (7.8 per cent) but significant difference in AUC of the active S-configuration (Froben> Ansaid). No significant differences between Ansaid and Froben were found for t,, or C,,, for the S-flurbiprofen. In bioequivalency studies of chiral drugs, stereospecific approaches provide a more accurate assessment of products. KEY WORDS
Flurbiprofen Bioequivalence Pharmacokinetics Enantiomers Stereospecific Stereoselective
INTRODUCTION Flurbiprofen, S,R-2-(2-fluoro-4-biphenylyl)propionic acid, is an orally effective nonsteroidal antiinflammatory drug (NSAID) with antipyretic and analgesic properties. It is useful in the management of mild to moderately severe pain syndromes and in arthritic conditions. Flurbiprofen is marketed in Canada as film-coated (Ansaid, the Upjohn Company of Canada, Don Mills, Ontario) and sugar-coated (Froben, Organon Canada Ltd, West Hill, Ontario) tablets. A previous study carried out on research lots of Ansaid and Froben 100 mg tablets provided evidence that Ansaid had a significantly shorter,,f than Froben. (D. J. Stalker and S. R. Pollock, personal communication). A difference 11 Present address, 420 East St, N, Sarnia, Ontario, Canada. Correspondenceto: Dr F. Jamali, Faculty of Pharmacy, University of Alberta, Edmonton, Alberta, Canada T6G 2N8 0142-2782/91/060435-11$05.50 0 1991 by John Wiley & Sons, Ltd.
Received 29 August 1990 Revised 12 February 1991
436
F. JAMALI ET A L .
in dissolution rates was identified between 100 mg tablets of Ansaid and Froben (K. S. Channer and J. P. Virgee, personal communication). In addition, the formulation of tablets has been shown to be important in oesophageal transit, with oesophageal clearance of film-coated tablets significantly better than for plain-coated tablets.' The objective of this study was to compare the oral bioavailability of Ansaid 100 mg tablets with that of Froben 100 mg tablets using marketed drug supplies. All of the available flurbiprofen products contain racemic drug. As only the S enantiomer possesses pharmacological activities*it seems essential to examine the bioavailability of the active enantiomer. Thus both stereospecific and nonstereospecific assays were applied to measure flurbiprofen in serum. Only limited data on the pharmacokinetics of flurbiprofen enantiomers are a ~ a i l a b l e .This ~.~ article will provide more information regarding stereoselective disposition kinetics of flurbiprofen in a relatively large sample size.
METHODS Products
Ansaid l00mg tablets (lot W688, The Upjohn Company of Canada, Don Mills, Ontario) and Froben 100mg tablets (lot 03788, Organon Canada Ltd, West Hill, Ontario) were purchased by a hospital pharmacist, independent of the study. Subjects
Twenty-three healthy male volunteers on no other medications participated in the trial. The mean age of the volunteers was 27.2 years (range 18-35 years). The mean weight was 71.8 kg (range 52.5-88.5 kg) and all were within 20 per cent of their ideal body weight according to the Geigy Scientific table^.^ Twelve of 23 volunteers smoked 2-25 cigarettes per day on a routine basis. Each participant was judged to be healthy after a history, physical examination, and laboratory tests (hematology, blood chemistry, and urinalysis). All subjects gave informed consent after a complete explanation of the protocol, approved by the University of Western Ontario's Health Sciences Standing Committee on Human Research. Study design In a two-way crossover, open-label design study with a 6 to 7 day washout period, each subject received one tablet (l00mg) of either brand on each of the two study days. The tablets were ingested with 100ml of tap water after a 10 h overnight fast (one cup of coffee was permitted on rising as long as
FLURBIPROFEN
437
this was taken on both study days). No alcohol-containing beverages were permitted in the 24 h period before a study, on the study day or in the 24 h after a study day. Standardized meals were provided on both study days. Breakfast was provided after the 2 h blood sample had been taken, lunch after the 4 h sample, a snack after the 8 h sample, and dinner after the 12h sample. Subjects were permitted to be ambulatory during the 2-24 h clinic stays. Smoking was permitted. Sampleprocessing and assays Approximately 15ml of venous blood samples for flurbiprofen assay were collected in red top Vacutainer tubes. The serum was harvested after the blood was centrifuged at 3000 rev min-I for 10 min at 4". The serum was divided equally into two portions in untreated plastic vials and glass vials pre-rinsed with 0.5-1.0 ml of 2 M sulphuric acid (to avoid hydrolysis of acyl glucuronides) which were allowed to dry overnight. The serum samples were stored at -20" until analysis. A general nonstereospecificassay6was used with some modifications. Briefly, the sample serum was mixed with internal standard, naproxen lOmg/lOOrnl HPLC-grade acetonitrile. After vortexing and centrifugation, the samples were injected directly into an HPLC. The column was a 10 cm stainless steel (4.6 mm id) 5 pm octadecyl-bonded silica (Partisil 5-ODs-3, Whatman Inc. Clifton, NJ, USA) attached to a 5 cm guard column of the same material with a 10 pm particle size. The mobile phase consisted of acetonitrile: 0.067 M KH2P04: triethylamine (32:68:0-02 v/v) with a flow rate of 1.0ml min-'. Flurbiprofen was detected at 254 nm. For the stereospecific determination, a previously reported HPLC assay was used.7 Treatment of data The two brands were compared on the basis of the maximum serum concentration achieved (C,,,), the time to reach the maximum serum concentration (t,,,), and the area under the 0-24 h serum concentration-time curve (AUC) which was calculated by the trapezoidal rule. A visual inspection of lag time between dosing and first detectable concentrations of flurbiprofen was also done. Stereoselective differences were determined by comparing the enantiomers pharmacokinetic indices. The t1,2of the terminal elimination phase of the serum concentration-time curves was estimated using a regression equation. Statistical significance of the observed differences between the enantiomers concentrations as well as between the pharmacokinetic indices were examined using the paired Student's t-test at a = 0.05.
438
F. JAMALI ET A L .
RESULTS Adverse effects Adverse effects of the medication were minor with subject 21 reporting 1 day of mild dysuria 2 days after dosing with Froben 100 mg. Subject 9 reported a feeling of a 'lump in my throat' persisting approximately 8 h after dosing on both study days. Bioavailability results
Nonstereospeclfic approach. No significant differences were found between the and AUC (Table 1, Figure 1). However, products in terms of their tmaxrCmax, as magnified in Figure 2, serum concentrations of Ansaid was significantly greater than Froben during the initial 30 min post-dosing period.
Table 1. Non-stereoselective bioavailability indices of flurbiprofen Ansaid Subject
Cmax
mg I-'
tmax
h
Froben AUC mg h I-'
Cmax
tmax
mgl-'
h
AUC mg h I-'
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
12.17 10.06 17.5 1 14.02 17.81 13.50 12.97 18.29 11.06 14.4 1 19.28 21.06 19.87 17.60 21.60 18.01 14.34 13.79 16.35 15.86 25.20 2 1.42 18.82
2.00 0.50 1 .oo 1.50 1.75 3.00 2.00 0.25 1.75 2.00 1.25 1.25 1.00 1 .oo 0-75 0.75 0.50 1.50 2-00 1-50 0.25 1 .oo 1.75
66.76 55.52 81.41 67.72 74.57 76.41 70.99 71.15 68.5 1 93.02 80.41 72.35 76.80 77.49 77.82 82.34 52.17 90.99 63.40 74.34 88.89 102.62 185.88
11.49 15.61 12.6 1 13.36 19.14 13.12 16.25 12.4 1 14.92 13.37 15.22 15.88 19.46 14.51 18.63 17.79 16.13 19.40 19.34 14.63 17.60 17.80 20.1 1
4.00 1 .oo 2.00 2.00 1 .oo 2.00 1.50 2.00 1.25 1.75 1.75 1.50 1.75 2.00 2.00 1.25 1.00 1 .oo 0.75 1.00 1 .oo 1 .oo 1.50
72.00 70.38 74.82 64.89 78.25 80.51 83.14 74.76 75.28 86.70 87.48 67.57 75.05 78.04 77.74 81.39 62.21 97.67 66.68 68.06 86.66 98.50 186.69
Mean SD
16.74 3.69
1-32 0.66
80.50 25.12
16.03 2.56
1.57 0.67
82.37 24.10
439
FLURBIPROFEN
2o
1
n
i E
W
Z
0 2 w I-
z
W 0
z
0 0
0
4
a
12
16
20
24
HOURS Figure 1. Mean nonstereospecific serum concentration-time curves of flurbiprofen following oral administration of Ansaid (+) and Froben (0).Error bars represent standard deviation of the means
n
i E W
Z
0
2 IY I-
Z
W
0 Z 0 0
HOURS Figure 2. Two-hour mean nonstereospecific serum concentration-time curves of flurbiprofen following oral administration of Ansaid (+)and Froben @). Error bars represent standard deviation of the means. The differences were significant at 0.25 and 0.50 h
440
F. JAMALI ET AL.
Stereospecijic approach. No significant differences were found between the products with respect to the observed t,,, and C,,, values of either enantiomers (Table 2 and 3, Figure 3). Similarly, the differences in the R enantiomer AUC values of the two products were insignificant. However, AUC of S enantiomer was significantly greater (7.8 per cent) after Froben than Ansaid (Tables 2 and 3). Also, as seen during the nonstereospecific approach, serum concentrations of both enantiomers were significantly greater after Ansaid as compared to Froben during the initial 30-min post-dosing period (Figure 4). With the exception of subject 21, the results of the bioavailability study were very comparable between the two methods when parameters for total (S+R) flurbiprofen were considered for each subject (r2 > 0.90 for Cmxand AUC with slopes of 0.98 and 1.0, respectively). Enantiomers pharmacokinetics Disposition kinetics of flurbiprofen was stereoselective. Following both products, S-flurbiprofen had greater AUC and longer t1,2as compared to its antipode (Tables 2 and 3, Figure 3). No significant amounts of glucuronide-conjugated enantiomers were found in plasma.
DISCUSSION Bioequivalency Based upon the nonstereoSpecific assay the only difference between the two products is a more rapid initial rise in concentration of Ansaid. This may be attributed to a faster dissolution for the film-coated product. The rapid release and absorption of active drug when NSAIDs have been film-coated has also been shown for naproxen.* Nevertheless, this initial difference did not amount to any significant dissimilarities in t,,, or C,,, values of the products. The observed small but significantly greater AUC for S-flurbiprofen (but not for R) following Froben as compared with Ansaid (Tables 2 and 3) is interesting because the S enantiomer has been established to be associated with the majority if not all of the anti-inflammatory activity of nonsteroidal anti-inflammatory drugs with the 2-arylpropionic acid structure.2This observation, although with unknown clinical significance, further emphasizes the importance of the application of proper analytical methods (i.e., stereospecific assays) in the bioequivalency or clinical pharmacology studies.’ The discrepancy between the two approaches is unlikely to stem from a difference in the release or absorption rate of the S-enantiomer. Both release and absorption processes are very likely governed by passive mechanisms hence the observed difference should have been seen for both enantiomers rather then for S-flurbiprofen a10ne.~For ibuprofen, another 2-arylpropionic acid derivative, which undergoes
8.20 1.61
Mean SD
35.13 37.92 42.20 34.32 43.91 45.35 38.81 44-58 3 1-47 46.59 40.74 39.92 40.02 45.48 48.38 44.67 35.84 52.42 40-18 45-06 29.07 61.72 101.20 44.74*7 13.86
1.75 2.00 0.75 1.25 2.00 3.00 2.00 0.25 1.75 2.00 1.50 1.25 1.oo 1.so 1*oo 1.00 0.75 3.00 2.00 1.75 1.oo 2.00 2.00
1.59 0.66
t Significantly different from Froben.
* Significantly greater than R-flurbiprofen.
6.49 6.01 9.38 7.53 9.64 6.44 6.31 9.44 6.13 6.58 7.9 1 9.13 10.27 8.36 10.91 9.31 9.19 7.14 9.60 8.34 5.06 9.83 9.71
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 6.89* 2.65
3.59 6.48 5.87 5.17 4.65 6.30 7.97 7.79 5.82 5.82 8.35 7.70 4.13 5.73 11.18 7.79 6.73 5.97 6.54 5.06 6.93 5.92 16.90 7.91 1.66
5.78 5.89 9.22 7.01 9.6 1 6.41 6.20 9.14 5.08 6.72 8.04 9.5 1 11.05 8.28 9.50 8.87 8.27 6.74 8.97 7.58 4.95 9.79 9-40 1.60 0.65
1.75 2.00 0.75 1.25 2.00 3.00 2.00 0.25 1.75 2.00 1.50 1.25 1.25 1.50 1*oo 1.oo 0.75 3.00 2.00 1.75 1.00 2.00 2.00 38-56 12.94
24.29 3 1.92 40.01 29.25 38.58 39.48 35.32 39.22 24.67 42.99 36.45 37.45 47.09 42.06 40.1 1 37.47 28.64 40.63 32.54 36.05 23.53 48.24 90.84 5.98 2.00
3.01 6.19 5.82 5.87 4.17 5.73 6.03 7.88 5.2 1 5.2 1 7.88 5.54 4.03 5.50 9.63 6.03 6.60 4-95 4.75 4.62 5.41 4.68 12.83 1.04 0-06
1.12 1.02 1.02 1.07 1 .oo 1.oo 1.02 1.03 1.21 0.98 0.98 0.96 0.93 1.01 1.15 1.05 1.1 1 1.06 1.07 1.10 1.02 1.oo 1.03 0.99 0.04
1.oo 1.oo 1.oo 1.oo 1.00
1
.oo
1.oo 1~00 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 0.80 1.oo 1.oo 1.oo 1.oo
1.17 0.1 1
1.45 1.19 1.15 1.17 1.14 1.15 1.10 1.14 1.28 1.08 1.12 1.07 0.85 1.08 1.21 1-19 1.25 1.29 1.23 1.25 1.24 1.28 1-11
Table 2. Pharmacokinetic indices of flurbiprofen enantiomers following administration of single dose of Ansaid
1.15 0.13
1.19 1.05 1.01 0.88 1.11 1.10 1.32 0.99 1.12 1.12 1.06 1.39 1.02 1.04 1.16 1.29 1.02 1.21 1.38 1.09 1.28 1.26 1.32
z
LEl
ti
-
E
6.93 7.42 6.40 6.54 9.23 6.38 8.74 6.03 5.57 6.47 7.39 8.12 8.60 7.20 7.99 8.88 7.19 9.97 10.07 7.94 9.5 9.05 11.09
7.94 1.43
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Mean SD
6.84* 2.84
48.2 1*t 13.89
1.67 0.69
6.30 5.59 6.08 4.71 4.85 6.60 6.54 9.49 6.79 5.10 4.99 6.66 5.63 6.03 6.19 5.97 6.48 6.54 7.79 5.87 5.97 7.97 19.25
57.54 42.29 40.93 35.02 47.69 46,34 42.10 5 1.52 36.42 43.69 43.36 39.69 44.77 44.42 40.88 49.19 39.76 55.81 37.65 43.41 58.17 64.39 103.68
h
4.00 1.50 3.00 2.00 1.25 2.00 1.25 2.00 1.oo 1.75 2.00 1.50 1.25 2.00 2.00 1.25 1.50 1.oo 1.oo 1.00 1.oo 1.50 1.75
t1/2
AUC mg h I-'
S
Tm, h
* Significantly greater than R-flurbiprofen. t Significantly different from Ansaid.
Cmax mgl-l
Subject
1.64 0.62
40.97 12.2 1
6.17 1.97
5.10 5.41 5.87 5.06 5.06 6.93 6.73 8.35 6.08 5.29 4.9 1 5.78 5.33 6.36 5.06 5.25 5.82 5.06 6.54 5.06 4.47 8.25 14.14
39.68 40.1 I 35.34 30.44 43.89 39.14 36.93 44.75 33.69 39.13 39.61 3 1.60 40.04 35.84 34.35 41.59 33.33 41.28 32.90 34.24 51.61 50.30 92.47 4.00 1.50 2.00 1.75 1.25 2.00 1.75 2.00 1.25 1.75 2.00 1 .50 1.50 2.00 2.00 1.25 1.25 1.oo 1.oo 1.oo 1.oo 1.25 1.75
5.76 7.71 6.15 6.71 9.36 6.09 8.57 5.79 5.78 6.63 7.46 7.73 8.55 6.81 8.06 8.29 7.27 9.51 9.97 7.23 10.14 9.13 10.23 7.78 1.43
h
t1/2
AUC mghl-l
Tmax h
Cmax mgl-'
R
1.02 0.15
1.18 0.09
1.45 1.05 1.16 1.15 1.09 1.18 1.14 1.15 1.08 1.12 1.09 1.26 1.12 1.24 1.19 1.18 1.19 1.35 1.14 1.27 1.13 1*28 1.12
1.oo 1.oo 1.50 1.14 1 .oo 1.oo 0.71 1.oo 0.80 1.oo 1.oo 1.oo 0.83 I .oo 1 .oo 1.oo 1.20 1.oo 1.oo 1.oo 1.oo 1.20 1.oo 1.20 0.96 1.04 0.97 0.99 1.05 1.02 1.04 0.96 0.98 0.99 1.05 1.01 1.06 0.99 1.07 0.99 1.05 1.01 1.10 0.94 0.99 I .08 1.02 0.06
AUC
Tmax
Cmax
SIR
Table 3. Pharmacokinetic indices of flurbiprofenenantiomers following administrationof single dose of Froben
1.10 0.13
1.24 1.03 1.04 0.93 0.96 0.95 0.97 1.14 1.12 0.96 1.01 1.15 1.06 0.95 1.22 1.14 1.11 1.29 1.19 1.16 1.34 0.97 1.36
t1/2
P
!-
9
c
5
3
.n
R
443
FLURBIPROFEN
10
8
6
4 A
_J
2
E
2
W
Z
g
1c
t-
4
f
Z w
E
u
Z
0 O
E
L
1
(
p
T
I 0
4
8
12
16
20
24
R to S inversion, it has been proposed that the inversion, and consequently the concentration of the active enantiomer, is influenced by the rate of absorption:'OJ1the slower the rate of absorption the greater the extent of inversion. This could explain greater AUC for the S enantiomer after Froben which has slightly slower rate of absorption than Ansaid (Figures 2 and 3). If so, one expects a corresponding reduction in AUC of the R enantiomer. This, however, may remain undetectable due to the small magnitude of the observed
F. JAMALI ET AL.
0.0
0.5
1 .o
1.5
2.0
HOURS Figure 4. Two-hour mean stereospecific serum concentration-time curves of flurbiprofen following oral administration of Ansaid (S A, R 0 ) and Froben (S A, R 0).Error bars represent standard deviation of the means
differences. Nevertheless, enantiomeric inversion, although a possibility, has not been suggested for flurbiprofen in human^.^ No detectable plasma concentration of S enantiomer was found following ingestion of R enantiomer. This inference, however, is not conclusive as despite undetectable plasma concentrations, approximately 10 per cent of R-ketoprofen doses have been found in urine as S-ketoprofen.I2 Stereoselective pharmacokinetics
In a previous report, pharmacokinetics of flurbiprofen enantiomers have been shown to be stereoselective in six male volunteers with the S enantiomer being predominant in plasma (AUC S/R, 1*13).3The observation reported here is in close agreement with that report. In this study, however, in addition to the stereoselectivity in plasma concentrations, a significant difference was also noted between the enantiomers with respect to their t l l Zwhich is in agreement with a recent report with a sample size of nine.4 Such a difference was not evident in subjects studied previously, due perhaps, to the small sample size. In summary, the mean 7.8 per cent difference in AUC of the pharmacologically active S-flurbiprofen observed between the two products may be of no regulatory or clinical significance. However, the presented data display, for the first time, the importance of using stereospecific assays in bioequivalency studies. From regulatory viewpoints, two bioequivalently different products may be found equivalent when assessed based upon nonstereospecific methods.
FLURBIPROFEN
445
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
K. S. Channer and J. P. Virgee, J. Pharm. Pharmacol., 337, 126 (1985). F. Jamali, Eur. J. Drug Metab. Pharmacokinet., 13, 1 (1988). F. Jamali, B. W. Berry, M. R. Tehrani and A. S. Russell, J. Pharm. Sci.,77,666 (1988). R. E. Small, S. R. Cox and W. J. Adams, J. Clin. Pharmacol., 30,660 (1990). K. Diem and C. Lentner, Ceigy Scientific Tables, Ciba-Geigy Ltd, Basle, Switzerland, 1973. pp. 712. F. Jamali, A. S. Russell, B. W. Berry and C. Lehmann, J. Chromatogr., 310,327 (1984). B. W. Berry and F. Jamali, Phurm. Res., 5 , 123 (1988). K. V. Gaismayer and G. Tausch, Forrschr. Med., 102,601 (1984). F. Jamali, R. Mehvar and F. M. Pasutto, J. Pharm Sci., 78,695 (1989). F. Jamali, N. N. Singh, F. M. Pasutto, R. T. Coutts and A. S. Russell, Pharm. Res., 5, 40 11988). M. T. Borin, S. R. Cox, J. M. Hageman and G. J. Szpunar, Pharm. Res., 10 (suppl.), 159s (1988). F. Jamali, A. S. Russell, R. T. Foster and C. Lemko, J. Pharm. Sci., 79,460 (1990).
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