Download Biowaiver extension potential to BCS Class III high solubility

European Journal of Pharmaceutical Sciences 22 (2004) 297–304
Biowaiver extension potential to BCS Class III high solubility-low
permeability drugs: bridging evidence for metformin
immediate-release tablet
Ching-Ling Cheng a , Lawrence X. Yu b,1 , Hwei-Ling Lee c , Chyun-Yu Yang d ,
Chang-Sha Lue e , Chen-Hsi Chou f,∗
a
b
Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan
Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Science, Rockville, MD 20857, USA
c Department of Public Health, Medical College, National Cheng Kung University, Tainan, Taiwan
d Department of Orthopedics, Medical College, National Cheng Kung University, Tainan, Taiwan
e Swiss Pharmaceutical Co. Ltd., Tainan, Taiwan
f Institute of Clinical Pharmacy, Medical College, National Cheng Kung University, 1 University Road, Tainan 70101, Taiwan
Received 7 August 2003; received in revised form 17 March 2004; accepted 29 March 2004
Available online 18 May 2004
Abstract
The biopharmaceutics classification system (BCS) allows biowaiver for rapid dissolving immediate-release (IR) products of Class I drugs
(high solubility and high permeability). The possibility of extending biowaivers to Class III high solubility and low permeability drugs is
currently under scrutiny. In vivo bioequivalence data of different formulations of Class III drugs would support such an extension. The
objective of this work was to demonstrate the bioequivalence of two marketed IR tablet products of a Class III drug, metformin hydrochloride,
that are rapidly dissolving and have similar in vitro dissolution profiles. The effect of race on the systemic exposure of metformin was
also explored. A randomized, open-label, two-period crossover study was conducted in 12 healthy Chinese male volunteers. Each subject
received a single-dose of 500 mg of each product after an overnight fasting. The plasma concentrations of metformin were followed for 24 h.
No significant formulation effect was found for the bioequivalence metrics: areas under concentration–time curve (AUC0–t , AUC0–∞ ) and
maximal concentration (Cmax ). The 90% confidence intervals for the ratio of means were found within the acceptance range of 80–125% for
the log-transformed data. Based on these results, it was concluded that the two IR products are bioequivalent. The pharmacokinetic parameters
of metformin in Chinese for both products were similar and were in good agreement with those reported for metformin IR tablets in other
ethnic populations. This study serves as an example for supporting biowaiver for BCS Class III drugs.
© 2004 Elsevier B.V. All rights reserved.
Keywords: Bioequivalence; Biopharmaceutics classification system; Biowaiver; Interethnic comparison; Metformin; Pharmacokinetics
1. Introduction
The biopharmaceutics classification system (BCS) is a scientific framework for classifying a drug substance based on
its aqueous solubility and intestinal permeability (Amidon
∗ Corresponding author. Tel.: +886-6-2353535x5684;
fax: +886-6-2373149.
E-mail address: [email protected] (C.-H. Chou).
1 The manuscript represents the personal opinions of the author and
does not necessary represent the views or polices of the Food and Drug
Administration.
0928-0987/$ – see front matter © 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.ejps.2004.03.016
et al., 1995). Based on the BCS, the US FDA issued a guidance for industry on waivers of in vivo bioavailability and
bioequivalence studies for immediate-release (IR) solid oral
dosage forms. It was recommended that sponsors may request biowaiver for IR solid oral dosage forms of highly soluble and highly permeable drugs (Class I) that exhibit rapid
in vitro dissolution (>85% in 30 min) (FDA, 2000).
For rapid dissolving dosage forms of Class III high
solubility-low permeability drugs, as they may behave
in vivo like an oral solution, membrane permeability is
expected to be the rate-limiting step in drug absorption.
Therefore, absorption kinetics from the gastrointestinal tract
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C.-L. Cheng et al. / European Journal of Pharmaceutical Sciences 22 (2004) 297–304
would be governed by drug biopharmaceutic factors and
physiologic factors, rather than by formulation factors, given
that excipients have no relevant effects on gastrointestinal
transit and permeability of drug (Yu et al., 2002). Thus it
has been suggested that the waiver of in vivo bioequivalence
studies be extended to Class III drugs (Blume and Schug,
1999; Yu et al., 2002). However, what kind of in vitro dissolution requirements should be set to ensure that the drug
release has no significant impact on in vivo bioavailability is
still unknown, and data available for supporting biowaivers
of Class III drugs are still limited (Yu et al., 2001).
Metformin hydrochloride is an oral anti-hyperglycemic
drug that has long been used in the management of
non-insulin-dependent diabetes mellitus. Metfromin has
high solubility in water (Bretnall and Clarke, 1998) and
low permeability to cell membranes (Chou, 2000; Nicklin
et al., 1996). Therefore, it can be classified as a BCS Class
III drug. The absorption of metformin is slow and incomplete following administration of an oral solution, and the
solution dosage form is bioequivalent to an IR tablet that
dissolved completely within 1 h (Sambol et al., 1996a).
Thus, it is evident that if the formulation of metformin IR
product is rapid dissolving, dissolution will not affect availability of metformin. Using the rationale of the BCS, it can
be argued that biowaivers can be granted for metformin IR
products on the basis of in vitro dissolution profiles.
The usual dosage for metformin is 250–500 mg three
times daily, up to a maximal of 3 g/day. The absolute
bioavailability of a 500 mg immediate-release tablet of
metformin hydrochloride given under fasting conditions
is 50–60%; with the maximal plasma concentration occurs at approximately 2.5 h following oral administration.
The absorption of metformin from gastrointestinal tract is
dose-dependent; and food decreases slightly both the rate
and extent of its absorption (Marathe et al., 2000a; Scheen,
1996). Side effects associated with metformin therapy are
primarily gastrointestinal in nature, such as nausea, vomiting, abdominal pain and diarrhea. Metformin has been
associated with severe lactic acidosis, especially in patients
with renal impairment (Scheen, 1996). Metformin is currently used in worldwide, however, its pharmacokinetic
behavior in Taiwanese subjects as well as its interethnic
comparison has not been reported in the literature. To ensure its interchangeability, it is important to assure that
the peak and systemic drug exposures are not significantly
different among various metformin formulations.
This work aims to substantiate the claim for biowaiver
extension to BCS Class III drugs, by using metformin as a
model drug. An attempt was also made to characterize the
pharmacokinetics of metformin in Chinese subjects and to
examine the ethnic sensitivity of metformin pharmacokinetics. To this end, an in vitro dissolution test for two marketed
IR tablet formulations of metformin was performed in three
pH (1.2, 4.5, 6.8) conditions and an in vivo absorption study
was conducted in healthy Chinese volunteers. As will be
shown below, a wavier was supported in vitro by the facts
that both formulations are rapid dissolved and have similar
dissolution profiles. The wavier was further justified by the
demonstration of in vivo bioequivalence.
2. Materials and methods
2.1. Materials
Both test and reference products are film-coated immediate-release tablets containing 500 mg metformin hydrochloride. The test product, Glucofit® 500 mg tablet (Lot
Number GUF700103), was manufactured by Swiss Pharmaceutical Co. Ltd., Taiwan. Glucophage® 500 mg tablet
(Lot Number 701SEN, Lipha Pharmaceuticals Ltd., UK)
was used as the reference product. Metformin hydrochloride reference standard (Lot 84H0451) was purchased from
Sigma (St. Louis, MO, USA). All chemicals were analytical grade reagents and used as received without further
purification. HPLC-grade solvents were obtained from
Fisher Scientific (Fair Lawn, NJ, USA). Water was purified through a Milli-Q reagent water system (Millipore,
Bedford, MA, USA) and used in the preparation of mobile
phase.
2.2. In vitro dissolution test
The dissolution tests were carried out on both products
using the dissolution Apparatus 1 (basket) of the USP 24
operated at 100 rpm under 37 ◦ C. Testing was conducted
in 1000 ml of each of the following dissolution media:
0.1N HCl, a pH 4.5 buffer and a pH 6.8 buffer. Samples
were withdrawn and filtered at 15, 30, 45, 60 min, and dissolved metformin concentrations were determined by UV
spectrophotometry at 233 nm.
2.3. In vivo bioequivalence study
2.3.1. Subjects
Healthy male volunteers between 20 and 40 years of age
who were within 20% of their ideal body weight for height
were enrolled in this study. All were judged healthy based
on medical history, routine physical examination, and results of clinical laboratory tests. Subject could not have a
history of diabetes mellitus or allergy to biguanides. Use of
prescription drugs were not allowed within 1 week prior to
dosing and during the study. No alcohol was allowed during
the whole study period. Other exclusion criteria included recent donation of blood or exposure to other investigational
drugs. A total of 12 subjects were enrolled; all were Chinese. The mean (±S.D.) age and weight of the subjects were
22.3 ± 3.0 years and 67.5 ± 9.3 kg. The study was conducted, in accordance with the Declaration of Helsinki, at
the medical center of National Cheng Kung University and
was approved by the Institutional Review Board of National
Cheng Kung University Hospital (Tainan, Taiwan). Written
C.-L. Cheng et al. / European Journal of Pharmaceutical Sciences 22 (2004) 297–304
informed consent was obtained from all subjects prior to
participation in the study.
2.3.2. Study design
A randomized, single-dose, open-label, two-period
crossover study design was used. Subjects were randomly
assigned to one of two groups taking either the test product
or the reference product. After a washout period of 1 week,
the subjects were crossovered. Following an overnight fasting period of at least 8 h, study drug (one 500 mg tablet) was
given orally with approximately 250 ml of water. Subjects
were permitted to take glucose solution 2 h after dosing.
Lunch and supper were served 4 and 8 h after drug administration. Blood samples were collected by an indwelling
cannula or by venipuncture immediately before dosing and
0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 h after dosing
during each period. The blood samples were centrifuged as
soon as possible and the harvested plasma was transferred
to 7 ml glass vials (Kimble® ). Plasma samples were then
stored in an upright position at −80 ◦ C until analysis. Safety
was assessed by clinical staff’s observation and by spontaneous reporting of adverse events throughout the study.
2.3.3. Drug analysis
Plasma concentrations of metformin (expressed as the
hydrochloride salt) were measured using a validated HPLC
method with UV detection as described elsewhere (Cheng
and Chou, 2001). In brief, to 0.5 ml of plasma samples
in a 10 ml culture tube were added to 10 ␮l of atenolol
(0.1 mg/ml, as the internal standard), 50 ␮l of 1N HCl
and 1.5 ml of acetonitrile. The contents of the tube were
vortex-mixed for 30 s and centrifuged at 1763 × g for 5 min.
The transferred supernatant was washed with 1.5 ml of
dichloromethane by vortex-mixing for 30 s. After centrifugation (1763×g, 5 min), an aliquot of the aqueous layer was
injected on to the column. The calibration curve was linear
over the range of 10–2000 ng/ml. The limit of quantitation
was 10 ng/ml. Both the intra-day and inter-day coefficient of
variation and the relative error were ≤12% in the pre-study
validation. In this study, duplicate quality control samples
at three concentrations (10, 100, and 1000 ng/ml) were included in each assay run. The coefficient of variation and
the relative error for quality control samples (n = 24) were
less than 13.7 and 3.8%, respectively. All post-dose samples
had concentrations above the limit of quantitation.
2.3.4. Pharmacokinetic analysis
Plasma concentration–time data for metformin were analyzed by conventional non-compartmental pharmacokinetic
techniques using a commercial program (WinNonlin Professional version 3.2, Pharsight Inc., Mountain View, CA,
USA). Maximal observed plasma concentration (Cmax ) and
the corresponding sampling time (tmax ) were determined by
visual inspection of the data. The apparent elimination rate
constant (λ) was estimated by linear regression (weighting
1/Cestimated ) of the log-transformed plasma concentrations
299
during the terminal log-linear decline phase. The apparent
terminal elimination half-life (t1/2 ) was calculated as ln(2)/λ.
The area under the plasma metformin concentration–time
curve from time zero to the last quantifiable point (AUC0–t )
was calculated using the linear trapezoidal rule. The AUC
extrapolated to infinity (AUC0–∞ ) was calculated as the
sum of AUC0–t and the last quantifiable point divided by
λ (C24 h /λ). The apparent oral clearance (Cl/F) was calculated as dose divided by AUC0–∞ . The apparent volume of
distribution (V/F) was calculated as (Cl/F)/λ.
2.3.5. Statistical analysis
For the purpose of bioequivalence evaluation, a two-way
analysis of variance model appropriate for crossover design
was used for AUC0–t , AUC0–∞ and Cmax . The statistical
model used to compare treatment groups included the formulation, period, sequence and the subject nested within
sequence as fixed effects. Cmax and AUCs were log transformed, and the resulting point and interval estimates of
means and mean differences were exponentiated to express
the results as geometric means and the ratios of geometric
means on the original scale of measurement. Statistical analysis was performed using WinNonlin (Professional version
3.2). The Type III sums of squares for all model effects were
used to determine statistical significance at the 0.05 levels.
Bioequivalence between test and reference formulations was
declared if the computed 90% confidence interval (CI) for
the ratio of test/reference was within the 80–125% interval
for log-transformed data. No additional analysis other than
descriptive statistics (mean ± S.D.) was performed on the
other pharmacokinetic parameters.
3. Results
3.1. In vitro dissolution test
The in vitro biopharmaceutical characteristics of the two
formulations were similar, as shown by the dissolution profiles in 0.1N HCl, pH 4.5 and pH 6.8 buffers (Fig. 1). The
cumulative percentage of metformin dissolved from test and
reference tablets was plotted as a function of time. Both
formulations released greater than 89% of their metformin
content within 30 min, with variability of less than 10% at
every time point measured. The dissolution profiles for the
two products were considered similar, based on the data
before 30 min using a model independent approach, as the
values of similarity factor f2 calculated were larger than 50
and f1 values were less than 7.2 under all physiological pH
conditions.
3.2. In vivo bioequivalence study
Metformin was safe and generally well tolerated. There
were no serious or severe adverse events reported in
this study and all adverse events were mild and resolved
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120
Percentage dissolved
100
80
60
40
20
0
0
15
30
45
60
75
Time (min)
Fig. 1. Mean in vitro dissolution profiles of metformin for 500 mg
immediate-release tablet of Glucophage® or Glucofit® in 0.1N HCl (䊊,
䊉) pH 4.6 (䊐, 䊏) and pH 6.8 (
, 䉱) buffer solution.
spontaneously. All volunteers enrolled completed the study
without incident and were included in the pharmacokinetic
and statistical analysis. Mean metformin concentration–time
profiles for Glucofit® and Glucophage® were shown in
Fig. 2. The mean concentration–time profiles for the two
formulations were remarkably similar and almost superimposable. After oral administration, both products were
readily absorbed, achieving measurable plasma metformin
concentration by the first post dose sampling time (0.5 h) in
all subjects. Peak plasma concentrations occurred at around
2.5 h after dosing, and thereafter the metformin concentration declined rapidly with a terminal half-life of 4–5 h. All
subjects had detectable plasma concentrations at 24 h, and
the ratios of AUC0–t /AUC0–∞ were all greater than 0.96.
The apparent oral clearance (l/h) and volume of distribution (l) for Glucofit® were 64.4 ± 10.3 and 464 ± 121,
respectively; and those for Glucophage® were 65.9 ± 11.8
1400
Concentration (ng/ml)
1200
1000
800
600
400
200
0
0
4
8
12
16
20
24
Time (h)
Fig. 2. Mean in vivo plasma concentration–time profiles of metformin
in 12 healthy Chinese subjects after oral administration of a 500 mg
immediate-release tablet of Glucophage® (䊊) or Glucofit® (䊉).
and 444 ± 113, respectively. The other pharmacokinetic
parameters were summarized together with those reported
in the literature in Table 1. For the primary bioequivalence parameters Cmax , AUC0–t , and AUC0–∞ , the test
formulation (Glucofit® ), was found to be bioequivalent to
the reference formulation (Glucophage® ) when using the
log-transformed data. The point estimates and 90% CIs for
the ratio of means were 1.03 (0.90–1.17), 1.02 (0.94–1.10)
and 1.02 (0.95–1.10) for Cmax , AUC0–t , and AUC0–∞ , respectively. No significant treatment effect was found, and
all the 90% CIs for the ratio of means for the primary
parameters were well within the FDA acceptable range of
80–125% for the log-transformed data. The results clearly
indicated that Glucofit® and Glucophage® are bioequivalent
and will produce similar clinical effects.
4. Discussion
4.1. Biowaiver likelihood of metformin:
biopharmaceutical considerations
4.1.1. Permeability and solubility
Metformin is highly soluble but poorly permeable to
biological membranes. It is a hydrophilic base with a partition coefficient, log P (n-octanol/aqueous buffer pH 7.4),
of −1.43 (Chou, 2000). Metformin is soluble to the degree
of one part in two parts of water (Bretnall and Clarke,
1998). The solubility of metformin is greater than 100 mg/ml
in Milli-Q water, 0.1N HCl, pH 4.5, pH 6.8 and pH 9.5
phosphate buffers. The highest dose strength of metformin
tablet (1000 mg) is soluble in 250 ml aqueous media over
the range 1–7.5. The pKa value of metformin (11.5) is extremely high, and it is therefore predominantly ionized and
occurs as the cation in the gastrointestinal tract and at physiological pH (Scheen, 1996; Chou, 2000). The lipophilicity
and degree of ionization of metformin suggest that its
transport across cell membrane could be limited. Indeed,
transfer studies with Caco-2 cells showed that the extent of
metformin transported was low (Dimitrijevic et al., 1999).
The Caco-2 permeability coefficient of metformin was
5.5 × 10−6 cm/s at pH 7.4 (Nicklin et al., 1996), which was
much lower than that for BCS Class I references such as
propanol (41.9 × 10−6 cm/s; Artursson, 1990). Using isolated perfused rat liver preparation, it was demonstrated that
hepatic uptake of metformin was limited by its sinusoidal
membrane permeability (Chou, 2000). It was shown previously that following administration of an oral solution the
absorption of metformin is slow and incomplete, and the solution dosage form is bioequivalent to the IR tablet (Sambol
et al., 1996a). Thus, membrane permeability of metformin,
rather than dissolution, is the rate-limiting step in its absorption. According to the BCS, metformin can be considered as
a Class III high-solubility low-permeability drug (Amidon
et al., 1995). Therefore, metformin was chosen as a model
drug to explore the biowavier potential of this class.
Reference
Study site
Na
Population
Product
Fasting
Cmax (ng/ml)
tmax (h)
AUC0–∞ (ng/ml h)
t1/2 (h)
Cheng et al. (this study)
Tainan, Taiwan
12
12
Chinese
Chinese
Generic
Glucophage®
Yes
Yes
1264 ± 302
1215 ± 225
2.2 ± 0.6
2.5 ± 0.6
7925 ± 1083
7832 ± 1530
5.0 ± 0.8
4.6 ± 0.9
Najib et al. (2002)
Amman, Jordan
24
24
–
–
Generic
Glucophage®
Yes
Yes
1036 ± 193
1016 ± 224
2.9 ± 0.9
3.0 ± 0.8
7293 ± 1573
6997 ± 1428
3.4 ± 0.8
3.3 ± 0.7
Jayasagar et al. (2002)
Tache et al. (2001)
Marathe et al. (2000a)
Warangal, India
Bucharest, Romania
Evansville, IN
12
12
28
–
–
White (24)/Black (5), 1 withdraw
Generic
Generic
Glucophage®
Yes
–
Yes
1465 ± 404
1260
879b
3.0
2.5
3d
8645 ± 2344
–
6116b
2.8
–
–
Yuen et al. (1999)
Penang, Malaysia
24
24
–
–
Generic
Glucophage®
Yes
Yes
1686b
1690b
2.2
2.3
9162b
9321b
3.3 ± 0.6
3.1 ± 0.7
Sörgel et al. (1998)
Germany
Germany
18
24
–
–
–
–
Yes
Yes
1190 ± 474
921 ± 263
–
–
7040 ± 1780
6750 ± 1820
–
–
Sambol et al. (1996b)
Caille et al. (1993)
Pentikäinen et al. (1979)
Zhi et al. (2002)
Gusler et al. (2001)
Di Cicco et al. (2000)
Karttunen et al. (1983)
Tucker et al. (1981)
San Francisco, CA
Montréal, Canada
Helsinki, Finland
USA?
Phoenix, AZ
Austin, TX
Kuopio, Finland
Sheffield, UK
24
24
5
21
14
16
8
4
–
–
–
White (19)/Other (2)
White (11)/Black (2)/Hispanic (2)
–
–
–
Glucophage®
Glucophage®
Generic
–
Glucophage®
Glucophage®
Glucophage®
Glucophage®
Yes
Yes
Yes
No
No
No
No
No
1029 ±
682 ±
1550 ±
778c
741 ±
917 ±
1000 ±
1020 ±
2.8 ±
2.4 ±
1.9 ±
1.95c
3.5 ±
3.5 ±
3
2.2 ±
6747 ±
4745 ±
9080 ±
6040c
5510 ±
6605 ±
–
6710 ±
5.1 ±
3.2 ±
2.6 ±
5.16c
6.1 ±
3.2 ±
2
5.4 ±
a
b
c
d
Sample size.
Geometric mean.
Steady-state value.
Median.
317
161
537
175
181c
311
340
0.8
0.9
0.9
0.7
1.5c
0.3
1758
1116
3444
1460
1169c
1820
1.8
0.5
0.4
1.8
0.5c
1.5
C.-L. Cheng et al. / European Journal of Pharmaceutical Sciences 22 (2004) 297–304
Table 1
Pharmacokinetic parameters (mean ± S.D.) of metformin in healthy subjects following oral administration of metformin hydrochloride as a 500 mg immediate-release tablet
301
302
C.-L. Cheng et al. / European Journal of Pharmaceutical Sciences 22 (2004) 297–304
4.1.2. Dissolution
For biowaiver of Class I high-solubility high-permeability
drugs, the rapid in vitro release requirement of at least 85%
dissolved in 30 min in 0.1N HCl, pH 4.5 and pH 6.8 buffers
is recommended. However, such criterion may not ensure
the bioequivalence of IR dosage forms of Class III drugs.
It has been suggested recently that the appropriate rapid
dissolution requirement should be 90% dissolved in 30 min
for Class III drugs, based on the consideration of disintegration of dosage form, dissolution of drug substance, the
gastrointestinal transit, and oral absorption processes (Yu
et al., 2001). The relationship between in vitro dissolution
and in vivo absorption of metformin dosage forms has been
explored previously. A Glucophage® -Retard tablet that dissolved 100% of label content within 1 h was shown to have
similar bioavailability as the aqueous solution of metformin
(Noel, 1980). Bioequivalence was demonstrated between a
metformin IR tablet and an oral solution (Sambol et al.,
1996a). Despite having considerable differences in dissolution profiles, the key absorption parameters (Cmax , AUC0–∞
and percentage excreted in urine) for a modified-release capsule of metformin, which released 90% of label content in
3 h at pH 6.8 phosphate buffer, were similar to that for the
Glucophage® IR tablet (Balan et al., 2001). These results
may be explained by the BCS. Because metformin is a Class
III drug, its in vivo absorption kinetics is governed mainly
by membrane permeability and not so much by drug release.
Thus, availability will be less sensitive to the variation in
dissolution characteristics. Hence, IR formulations/dosage
forms of metformin with differing in vitro dissolution will
not necessary display dissimilar in vivo absorption. In this
study, the test and reference metformin IR products dissolved rapidly with more than 89 and about 100% of the
active substance dissolved within 30 min and 1 h, respectively, using USP apparatus 1 at 100 rpm in 0.1N HCl, pH
4.5 and pH 6.8 buffers (Fig. 1). Their in vitro dissolution
profiles were judged sufficiently similar as assessed by the
f2 test. Based on the theoretical considerations and practical
in vitro–in vivo relationships for various metformin formulations, bioequivalence would be expected for the two IR
products examined in this study given their rapid and similar
dissolution profiles.
4.1.3. Excipient
Low permeability drugs are often associated with
site-dependent absorption characteristics, therefore, the rate
and extent of absorption for these drugs will depend on
their gastrointestinal transit. Previous studies showed that
metformin is predominantly absorbed from the small intestine, with very low absorption from the stomach and the
colon. And the extent of metformin absorption is increased
as the gastrointestinal motility is slowed (Vidon et al., 1988,
Marathe et al., 2000b; Stepensky et al., 2001). Thus, it is important that the excipients used should not have significant
effects on the gastrointestinal motility and permeability in
order to be considered for biowaiver. It was reported that a
survey of the FDA data over 10 BCS Class III drugs shows
that most commonly used excipients in solid dosage forms
have no significant effect on absorption (Yu et al., 2002).
The results of Rege et al. (2001) demonstrated that several
commonly used excipients in IR dosage form did not have
significant effect on Caco-2 transport of low permeability
drugs. It was shown that non-ionic surfactants (Solulan
and polysorbate) are active as absorption enhancers as they
significantly increase the transepithelial permeability of
metformin in Caco-2 cell monolayers (Dimitrijevic et al.,
1999). Generally, the conventional excipients used in metformin oral IR dosage forms (e.g. povidone, magnesium
stearate, hydroxypropyl methylcellulose (coating)) do not
significant affect gastrointestinal motility and membrane
permeability of metformin.
4.1.4. Transporters, presystemic metabolism
Metformin exhibits dose-dependent absorption. The
mechanisms for nonlinearity of metformin absorption
remain unknown. Dose-dependent, saturable kinetics in
drug absorption may result from limited drug solubility,
carrier-mediated uptake, Pgp/transporters-mediated intestinal secretion, and intestinal metabolism of drugs (such
as by CYP 3A4). Because metformin is rapidly dissolved
under the gastrointestinal pH, dose-dependent absorption
derived from limited drug solubility for metformin is unlikely. No active uptake or efflux transport system in gastrointestinal tract for metformin has been demonstrated so
far. The transepithelial transport of metformin in the intestine is mainly by passive paracellular route of transfer,
and it is not transported by the active imino acid transport
system (Nicklin et al., 1996). Net secretion of metformin
from blood into the gut lumen was negligible as no drug
was recovered in the feces after intravenous administration
(Tucker et al., 1981). Upon absorption, metformin does not
undergo first-pass metabolism. The hepatic extraction and
biliary secretion of metformin is negligible (Chou, 2000).
It is not metabolized and is eliminated mainly via urine
(Scheen, 1996). Thus, the impact of transporter and presystemic metabolism on metformin absorption seems to be
insignificant.
Therefore, from a biopharmaceutic point of view the
likelihood of bioequivalence for different metformin IR
products is high. Given that the dissolution profile is similar and excipients have no relevant effects on absorption,
a biowaiver of metformin IR products can be considered.
Indeed, the study of Sörgel et al. (1998) demonstrated the
similarity in systemic absorption of metformin between
two different oral products manufactured at two different countries. Furthermore, as the formulations used in
the present work contain only the conventional excipients
(avicel, providone, magnesium stearate and hydroxypropyl
methylcellulose), the demonstration of bioequivalence between the two rapid dissolved IR products of metformin
gave a further support for the biowaiver of Class III
drugs.
C.-L. Cheng et al. / European Journal of Pharmaceutical Sciences 22 (2004) 297–304
2000
The pharmacokinetics of metformin has been well characterized in Caucasians (Scheen, 1996). However, pharmacokinetic studies of metformin conducted in Chinese are
limited and few such data have been reported in the literature. So far, no studies of metformin pharmacokinetics with
respect to race have been performed. Therefore, interethnic
comparison on metformin pharmacokinetics is of great interest, as it may provide evidence for bridging.
Intestinal absorption of metformin is mainly by passive transfer, and as such ethnic differences in passive
uptake would not be anticipated. Metformin is not a prodrug, it is not metabolized and does not bind appreciably
to plasma protein, therefore, metabolism-based and protein binding-related drug interactions are unlikely. The
inter-subject variation in absorption, in terms of Cmax and
AUC0–∞ were low (less than 25%). Following oral administration, there were no significant differences in metformin
kinetics between healthy subjects and type II diabetic patients with normal renal function, or during multiple-dose
regimen versus single-dose treatment (Tucker et al., 1981;
Sambol et al., 1996b). There were no gender differences in
metformin pharmacokinetics (Sambol et al., 1996b). Overall
these pharmacokinetic properties of metformin suggest that
its absorption and systemic exposure would not be highly
susceptible to variations in conventional oral IR formulations and would be none to minimally ethnically sensitive.
In this study eight subjects showed double peaks in their
plasma metformin profiles after oral administration of both
tablet formulations. The first and second peaks occurred at
around 1.5 and 3 h, respectively. The presence of double
peaks may have been due to variability of gastric emptying
and small intestinal transit time. Such a phenomena is not
uncommon for Class III drugs and can be seen in studies in
other ethnic populations (Sambol et al 1996a; Marathe et al.,
2000b; Gusler et al., 2001).
The pivotal kinetic parameters of absorption from various
IR metformin tablets reported in literature studied with different ethnic populations were compared and summarized in
Table 1. The pharmacokinetic parameter estimates of metformin in Chinese for both the generic formulation and the
innovator product were similar and were comparable to those
in other ethnic populations for various formulations manufactured worldwide. On examining the data in Table 1, the
relationship between the peak exposure Cmax and the systemic exposure AUC0–∞ is worth noting. As shown in Fig. 3,
a plot of Cmax versus AUC0–∞ in various ethnic populations is approximately linear for metformin. And for most of
the data, the value of Cmax was within 900–1300 ng/ml and
that of AUC0–∞ was within 6000–8000 ng/ml h. The spread
of Cmax and AUC0–∞ of metformin among different ethnic
groups dependents on not only the variability in bioavailability of the drug products, but also the variabilities in drug
assay used and bodyweight of subjects employed. The find-
1600
Cmax (ng/ml)
4.2. Ethnic sensitivity of metformin pharmacokinetics:
bridging evidence
303
1200
800
400
4000
6000
8000
10000
12000
AUC (ng/mlxh)
Fig. 3. Relationship between maximal plasma concentration (Cmax ) and
area-under plasma concentration time curve (AUC0–∞ ) after oral administration of a 500 mg immediate-release tablet of metformin hydrochloride
in various ethnic populations. Data are mean (S.E.) values from Table 1
((䊏) this study; (䊉) literature data).
ing that Cmax and AUC0–∞ are linear correlated suggests
that absorption and disposition of metformin IR tablets in
various ethnic populations are similar.
In conclusion, for rapid dissolving IR dosage forms of
BCS Class III drugs, the bioequivalence likelihood between
different formulations with commonly used excipients is
high, and hence waiver for in vivo bioequivalence can be
considered. In the present study, a biowaiver was suggested
by the in vitro dissolution profiles, and was justified by the
in vivo bioequivalence data. The demonstration of bioequivalence between two IR tablets of Class III drug metformin
in healthy Chinese subjects serves as an example for supporting biowaivers for such cases. Furthermore, the pharmacokinetic parameters of metformin in Chinese were similar
to those reported for a variety of metformin tablets studied
in other ethnic populations.
Acknowledgements
The project was supported in part by National Science
Council of Taiwan (NSC86-2314-B006-032, NSC87-2314B-006-033) and Swiss Pharmaceutical Co. Ltd., Taiwan. We
thank Miss Chiu-Yen Dai for technical assistance. The corresponding author thanks Pharsight Inc. for the approval of
Institute of Clinical Pharmacy, National Cheng Kung University as the ACE site-Taiwan and the free access to WinNonlin Prof. 3.2 program.
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