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UDC: 615.212:615.015.4

ORIGINAL ARTICLE

A pharmacokinetic comparison of three


pharmaceutical formulations of nimesulide in
healthy volunteers
Duan Jovanovi*, Vesna Kilibarda*, Veljko Todorovi, Olivera Potrebi
Military Medical Academy, National Poison Control Centre, *Institute of Toxicology and

Pharmacology, Clinic of Emergency and Clinical Toxicology and Pharmacology, Belgrade

Background/Aim. Switching the patient from one pharmaceutical formulation of the same
drug to another, may lead to therapeutic inadequancy in some cases. To minimize the risk,
careful pharmacokinetic studies are desired in the pre-registration period and afterwards.
Methods. A randomized, crossover design with one-week wash-out period between each dose
was applied. Serum samples, obtained before dosing and at various appropriate time points
up to 15 hours, were analyzed for nimesulide content by a high-performance liquid chromatographic method with ultraviolet (UV) detection. The pharmacokinetics and relative bioavailability of three different pharmaceutical formulations containing nimesulide, manufactured by the same pharmaceutical factory, were studied prospectively in 12 healthy subjects of
both sexes. A single 100-mg oral dose of nimesulide was given to the volunteers in the form of
conventional tablets, mouth dissolving tablets or as a suspension. Analysis of variance, power
analysis, 90% confidence intervals, and two one-sided tests were used for the statistical analysis of pharmacokinetic parameters. Results. The tolerability of all preparations was excellent.
The respective confidence intervals of the ratios of geometric means of Cmax and AUC0- of
nimesulide were out of acceptable limits either for conventional tablets in comparison with
suspension or for mouth dissolving tablets when compared with conventional tablets. A comparison of mouth dissolving tablets with suspension showed a statistically significant difference between Cmax values (suprabioavailability of mouth dissolving tablets), while the point
estimate of the ratio of geometric means of AUC0- was 0.945 with the corresponding 90%
confidence interval of 0.9020.991. At the 5% level of significance, there were no differences
between the formulations under the study in times elapsed to peak serum concentrations, as
revealed by the non-parametric Wilcoxon signed ranks test. Conclusion. Only a 90% confidence interval for the relative differences of log-transformed AUC0- values of nimesulide absorbed from mouth dissolving tablets vs. suspension was included in the 80% to 125% interval
proposed by the Food and Drug Administration (FDA). On that basis, mouth dissolving tablets (Nimulid-MD) were considered bioequivalent to Nimulid suspension according to the
extent of drug absorption. Concerning the comparable amounts of nimesulide available in the
systemic circulation after application of these formulations the one might not expect therapeutic failure after switching the patient from one to another.
Key words:

anti-inflammatory agents, non-steroidal; chemistry,


pharmaceutical; dose-responce relationship, drug;
pharmacokinetics; biological availability; therapeutic
equivalency.

Introduction
Nimesulide is a synthetic sulfonanilide derivative. It
belongs to a class of non-steroidal anti-inflammatory drugs

(NSAID) which selectively inhibit cyclooxygenase-2 but,


also, interfere with the production/action of mediators other
than prostaglandins such as enzymes, toxic oxygen derivatives, cytokines, platelet-activating factor and histamine (1,

Jovanovi D, et al. Vojnosanit Pregl 2005; 62(12): 887893.

888

2). A combination of a variety of mechanisms makes nimesulide a NSAID with marked anti-inflammatory, analgesic
and antipyretic activities (2, 3). Several recent experimental
studies have also demonstrated a significant neuroprotective
effect of nimesulide on chronic cerebral hypoperfusion (4),
global cerebral ischemia (5,6), diffuse traumatic brain injury
(7, 8) or cerebral infarction induced by permanent middle
cerebral artery occlusion (9).
The pharmacokinetic profile of orally administered
nimesulide is characterized by rapid and complete absorption, the rate and the extent of which do not differ significantly whether the drug was administered in a tablet or in a
suspension form. The time to reach maximal concentration
was reported to vary from 1.9h in children to more than
2.5h in healthy volunteers (3).
Nimesulide is 99% bound to human plasma proteins,
mainly albumins and it is principally distributed in the extracellular fluid compartment. The drug undergoes extensive
metabolism in the liver. Metabolic biotransformation can occur at both the phenoxy ring moiety and the aromatic nitro
group. The principal metabolite is 4-hydroxynimesulide,
which contributes to the anti-inflammatory activity of the
compound. Another degradation product, 2-(4-hidroxyphenoxy)-4-N-acetylamino-methansulfonanilide, was recently
identified in human urine and it is produced in much lower
concentrations.
Only 1% to 3% of the dose is excreted unchanged in
the urine, while the metabolites are eliminated mainly via
the urine (70%) or the feces (20%) in both free and conjugated form. The terminal elimination half-life of nimesulide
is shorter in children than in adults (approx. 2.4h vs. up to
5h) while the elimination half-times of metabolites are
nearly 2-times higher than that of the parent compound (3).
The purpose of this study was to evaluate the tolerability, pharmacokinetic property and comparative bioavailability of the three different pharmaceutical formulations of
nimesulide, all manufactured by the drug company Panacea
Biotec Ltd. from India, that are available at the Serbian
market. Particular attention has been made to the pharmacokinetic profile of flavoured dispersible tablets (MD tablets) with fast mouth dissolving characteristics thereby providing immediate relief of the drug (10). Although this had
not been a classic bioequivalence study, it was of therapeutic interest to compare their bioavailability with that of the
liquid formulation (suspension) which is usually thought to
be a 100% bioavailable.
Methods
A single-dose, open-label, randomized, six-sequence,
three-period crossover study design was used to evaluate
the bioavailability of nimesulide, prepared either as a 100mg conventional tablets (Nimulid tablets), 100-mg mouth
dissolving tablets (Nimulid-MD tablets) or a 50 mg/5 ml
suspension (Nimulid suspension). Twelve subjects of
both sexes in good physical condition, as determined by the

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complete medical and laboratory examinations before the


study, were enrolled and provided written informed consent
prior to any study related procedure. The study was approved by the Drug Commission and the Ethics Committee
of the Military Medical Academy, on September 20, 2001.
The enrolled subjects were randomly assigned to one of
the six sequence groups such that upon the completion of the
study each subject received all three regimens. Dosing in each
of the three consecutive periods was separated by 7-day washout period. A single dose of 100 mg nimesulide (one conventional tablet, one MD tablet or a 10-ml volume of suspension)
was given with 200 ml of non-carbonated mineral water following an overnight fast of at least 10 hours.
Venous blood samples (approx. 8 ml) were collected
prior to dosing (hour 0) and afterwards at time-points 0.33,
0.66, 1, 1.5, 2, 3, 4, 6, 8, 12 and 15 hours. The samples were
centifuged within one hour of collection and the serum was
separated and frozen at -20C until assayed.
Assay method
The High Performance Liquid Chromatography
(HPLC) set was equipped with a pump (Model 2150, LKB,
Bromma, Sweden), an automatic sample system (Model
AS-100, Bio-Rad Laboratories, Inc., Hercules, CA, USA), a
variable wavelength UV detector (Model 1801, Bio-Rad
Laboratories, Inc., Hercules, CA, USA) and an integrator
(Model 2221, LKB, Bromma, Sweden). For the acquisition
and integration of analytical data, a Bio-Rad Value Chrom
software, operated by Pentium microprocessor, was used.
Separations were performed on a reverse phase column
(BioSil C18 HL, 4.6 x 250 mm; Bio-Rad Laboratories, Inc.,
Hercules, CA, USA) at the ambient temperature.
The HPLC assay for determination of unchanged
nimesulide was fully developed and completely validated in
our laboratory. Its development, however, had been based
on the data published by Gupta (11) but due to differences
in the equipment and materials being on disposal, it had to
be generally modified.
The HPLC analysis was performed by using a mobile
phase consisted of 0.01M ammonium-dihydrogen-orthophosphate and acetonitrile (1:1), previously filtrated and degassed by a membrane degasser. The flow rate was 1.0
ml/min, an injector loop volume was 20 l, and an UV detector wavelength set at 300 nm throughout the assay. Under these conditions the retention time of nimesulide was
about 6.47 min. All the chemicals were of HPLC, and p.a.
purity, and had been purchased commercially.
After being refrigerated, the samples were allowed to
melt spontaneously at room temperature. Aliquots of 0.5 ml of
serum were dispensed into glass tubes and were deproteinized
using 0.5 ml of acetonitrile. The mixture was strongly vortexed
for 60 seconds to ensure adequate mixing and afterwards centrifuged at 8000 g for 2 minutes. The obtained supernatant
amounting 20-l was injected into the HPLC system and further analyzed using the validated HPLC-UV method. Standard
solutions (range of concentrations 0.0510.0 g/ml) and

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spiked serum samples (range of concentrations 0.15.0 g/ml)


were also determined under the same assay conditions.
Pharmacokinetic analysis
The pharmacokinetic parameters of nimesulide were
estimated using non-compartmental techniques. The peak
plasma concentration (Cmax) and the time elapsed to peak
concentration (tmax) were obtained directly from the data.
The elimination rate constant (ke) was obtained from the
slope of the terminal log-linear phase of the semilog plot of
concentration versus time. Half-life (t1/2) was calculated as
ln2/ke (ln2 = 0.693). The area under the nimesulide serum
concentration-time curve (AUC0-15) was computed using the
linear trapezoidal rule while the area under the serum concentration-time curve from time 0 to the infinite time
(AUC0-) was calculated as the sum of AUC0-15 and Ct/ke,
where t was the time of the last measurable concentration
(Ct) and ke was the elimination rate constant.
Parameters Cmax, tmax and AUC0- were accepted as the
main variables, while the values of AUC0-15, residual areas
[AUC0-15/AUC0- * 100], ke and t1/2 served as the secondary
pharmacokinetic objectives.
Statistical analysis
The following main pharmacokinetic parameters,
which completely describe the rate and the extent of absorption of nimesulide, derived from the individual serum
concentration-time profiles were subjected to statistical

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Bioequivalence between the formulations was accepted if the back transformed 90% confidence intervals for
the geometric mean ratios od AUC0- and Cmax had follen
within 0.801.25 range (1214) and if the differences in tmax
between the two formulations had been not statistically different (p > 0.05).
Results
HPLC method
Under the described assay conditions, linearity was
observed in serum standard curves of nimesulide over the
range of 0.05 10.0 g/ml with a correlation coefficient
greater than 0.999. The lower limit of quantification (LOQ)
of unchanged nimesulide was 0.1 g/ml while the limit of
detection was 0.05 g/ml of serum. Concentrations below
LOQ were reported as 0.0 g/ml. The mean recovery of extraction of nimesulide from serum samples ranged from
93% to 109%. The same working standard solutions had been
stable during a 5-day working period when kept in the refrigerator.
Study in healthy volunteers
A total of 12 subjects, whose demographic characteristics are summarized in Table 1, were selected to participate in the study. There were no differences in their age,
weight or height that might compromise the validity of the
planned pharmacokinetic trial.
Table 1

Demographic data of subjects (n = 12)


Mean*
SE
Min.
Max.
CV (%)

Age (years)
37.3
2.7
21.0
49.0
25.2
Males, n = 9

Weight (kg)
Height (cm)
88.0
178.8
5.9
2.7
60.0
160.0
110.0
191.0
23.2
5.3
Females, n = 3

*Mean arithmetic mean, SE standard error of the mean, CV coefficient of variation

analysis: Cmax, AUC0- and tmax. The comparison of secondary kinetic variables was only descriptive.
Following logarithmic transformation of AUC0- and
Cmax the values were subjected to analysis of variance
(ANOVA) including terms for subjects, treatment (sequence) and period. For evaluation of bioequivalence the
point estimates and 90% confidence intervals for the difference between test and reference formulations were constructed using the residual mean square error, obtained
from the multifactorial ANOVA. The point estimates and
the 90% confidence intervals were then back transformed
to give estimates of the ratio of the geometric means and
the corresponding 90% confidence intervals for the ratios
of the two formulations in the comparison. A nonparametric test (Wilcoxon Signed Rank's Test) was performed for tmax.

The mean serum concentration-time profile of nimesulide absorbed from the 3 different pharmaceutical preparations is shown in Figure 1. Marked differences were observed between the amounts of drug that had reached the
systemic circulation during the period of 15 hours. However, the tolerability of all three preparations containing
nimesulide was reported as excellent.
The relevant pharmacokinetic parameters of nimesulide
for each preparation are listed in Table 2. As it can be seen,
the residual area (relation between AUC0-15 and AUC0-) of
nimesulide (7.3% suspension, 5.5% conventional tablets,
5.0% MD tablets) accounted for less than 20% of the area
from time 0 to the time of the last measurable concentration.
Therefore, the stated criterion (AUC0-15/AUC0- * 100 > 80%)
was fulfilled and the residual area had no sizeable impact on
the calculation of AUC0- and, thus, on bioavailability.

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Fig. 1 Mean (SE) concentration vs. time profiles of nimesulide in serum after oral administration of a 100-mg dose of
suspension NimulidTM, conventional tablets NimulidTM or Nimulid-MDTM tablets to 12 healthy volunteers of booth sexes.

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The rate of nimesulide absorption from the tested


pharmaceutical formulations, as well as their half-lives of
the terminal phase, agreed very well after the application of
the three nimesulide-containing preparations. Marked differences in the maximal concentrations were noted between
MD tablets and the other two formulations following the
same dosages of the drug.
The statistical evaluation of the main pharmacokinetic
variables, which describe the rate and the amount of absorption of nimesulide, is presented in Table 3. The respective point estimates of the ratios of geometric means of logtransformed Cmax and AUC0- of nimesulide were 0.655 and
0.498 (conventional tablets vs. suspension), 1.244 and 0.945
(MD tablets vs. suspension), and 1.827 and 2.103 (MD tablets vs. conventional tablets). The corresponding 90% confidence intervals were 0.2600.607, 0.3350.603,
1.0041.542, 0.902-0.991, 1.3582.457 and 1.5752.810,
respectively. For the median tmax values, at a 5% level of
significance, there were no significant differences between
the formulations in the study, as revealed by the nonparametric Wilcoxon signed ranks test.
Table 2

*Mean ( SE) values of pharmacokinetic parameters of nimesulide after the ingestion of a single 100-mg dose of conventional
tablets Nimulid, mouth dissolving tablets Nimulid-MD and suspension Nimulid

Parameter

Suspension
Mean
SE
Cmax (g.ml-1)
4.53
0.67
tmax (h)
3.0
0.4
ke (h-1)
0.2214
0.0201
t1/2 (h)
3.5
0.4
AUC0-15 (g.h.ml-1)
34.75
6.55
AUC0- (g.h.ml-1)
38.44
7.55
Residual area (%)
7.3
1.7
* Mean arithmetic mean, SE standard error of the mean

Formulation
Conventional tablets
Mean
SE
4.11
1.03
2.8
0.5
0.2764
0.0327
2.8
0.2
24.70
8.09
26.56
8.95
5.5
1.5

MD tablets
Mean
5.88
2.8
0.2645
3.0
33.86
36.01
5.0

SE
0.98
0.3
0.0318
0.3
6.17
6.80
1.3

Table 3
Statistical evaluation of bioequivalence of nimesulide from the Nimulid 100-mg conventional tablets, Nimulid-MD 100-mg
mouth dissolving tablets or Nimulid suspension (50-mg/5 ml)
Pharmacokinetic parameter
AUC0-
tmax
Cmax
Nimulid tablets vs. Nimulid suspension
Point estimate of the ratio of geometric means
0.655
0.498
90% confidence interval of the ratio of geometric 0.260 0.607
0.335 0.603
means*

p = 0.5465
Wilcoxon signed ranks test
Nimulid-MD tablets vs. Nimulid suspension
Point estimate of the ratio of geometric means
1.244
0.945
90% confidence interval of the ratio of geometric 1.004 1.542
0.902 0.991
means*

p = 0.5050
Wilcoxon signed ranks test
Nimulid-MD tablets vs. Nimulid tablets
Point estimate of the ratio of geometric means
1.827
2.103
90% confidence interval of the ratio of geometric 1.358 2.457
1.575 2.810
means*

p = 0.7518
Wilcoxon signed ranks test
Statistical test

* - Acceptance range (bioequivalence):

- Bioequivalence:

0.80 1.25
p > 0.05

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Discussion
The analysis of the assay data indicated that the chosen
HPLC-UV method was simple, precise and enough accurate
for performing a valid bioequivalence study. According to
the literature, its sensitivity was comparable to the results of
the HPLC methodologies that had been applied so far to
determine nimesulide concentration by other investigators
(1520). As expected, however, the HPLC method we used
was less sensitive than liquid chromatography coupled to
tandem mass spectrometry (21).
Twelve subjects were arbitrarily chosen to participate
into the study. That number corresponded to the smallest
sample that is accepted as sufficient to assess bioequivalence (22, 23) and might represent a reliable number of participants for the bioequivalence decision. The post-study
calculations based on the log-ANOVA error data [AUC0-
CV-intra = 6.68%; suspension vs. MD tablets] revealed a
sample size of 7 subjects to be quite enough to show the difference of 20% between the AUC0- values of the test and
the reference articles. The type I and type II errors would
not exceed 5% and 20%, respectively.
The overall pharmacokinetic profile of nimesulide in
the present study, independently from the pharmaceutical
formulation being used, was close and in agreement with
the data previously published for oral nimesulide preparations in the relevant publications (3, 1518, 2429). However, on the basis of maximum serum concentrations and
AUC0- values of nimesulide it was concluded that they had
been significantly different after the administration of suspension and conventional tablets. Oppositely, the total
amount of nimesulide (AUC0-) absorbed from the suspen-

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sion and MD tablets did not differ significantly with the


power (derived from ANOVA) greater than 0.999.
Only 90% confidence intervals for AUC0- geometric
mean ratios of MD tablets, when compared to suspension,
were included in the 80% to 125% interval proposed by the
U.S. Food and Drug Administration (12, 13) and the difference between tmax values was statistically insignificant. On
that basis, tablets Nimulid-MD were considered bioequivalent to suspension Nimulid according to the extent of
absorption of nimesulide. The differences in Cmax values,
indicating suprabioavailability of MD tablets according to
the rate of absorption, were judged not to be therapeutically
important since, nimesulide is not a medicine which pharmacodynamic action is closely related to the level of maximal concentrations in the blood.
Conclusion
From the pharmacokinetic point of view, concerning the
total amount of drug that is available at the site of action, suspension and MD tablets could be marked as interchangeable
by a physician and might not be expected to produce therapeutic failure after switching the patient from one to another.
An increased maximal concentration in the serum after MD
tablets would definitely not increase the toxicity level of
nimesulide due to its wide therapeutic window in patients.
Acknowledgment
The authors wish to thank Ms. Vera Mladenovi, Mrs.
Sneana Stevanovi and Mr. Dragoslav Savi for their perfect and helpful assistance during the clinical and analytical
phases of the study.

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Apstrakt
Jovanovi D, Kilibarda V, Todorovi V, Potrebi O. Vojnosanit Pregl 2005; 62(12):
: 887893.
FARMAKOKINETIKO POREENJE TRI FARMACEUTSKA OBLIKA
NIMESULIDA KOD ZDRAVIH DOBROVOLJACA
Uvod/Cilj. Prevoenje bolesnika sa jednog na drugi farmaceutski oblik istog leka,
moe u pojedinim sluajevima, rezultirati promenjenim terapijskim efektom. U cilju
smanjenja ovakvih rizika, u preregistracionom periodu, ali i nakon putanja u promet leka, nuno je sprovesti ozbiljna farmakokinetika ispitivanja. Metode. Izvedeno je randomizovano i unakrsno ispitivanje sa wash-out periodom od sedam dana. Uzorci seruma uzimani su pre davanja lekova, a nakon toga, u definisanim
vremenskim takama, tokom 15 sati. Prospektivna studija obuhvatila je 12 zdravih
osoba oba pola u cilju ispitivanja farmakokinetike i relativne bioloke raspoloivosti
nimesulida primenjenog u tri razliita farmaceutska oblika, koje proizvodi isti proizvoa. Dobrovoljcima je davana jednokratna doza nimesulida od 100 mg, u obliku
standardnih tableta, tableta koje se tope u ustima ili suspenzije. Odreivanje nime-

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893

sulida vreno je tenom hromatografijom visoke rezolucije sa UV detekcijom. Za


statistiku analizu izraunatih farmakokinetikih parametara koriene su: analiza
varijanse, power analiza, 90% intervali poverenja i dvostruki, jednostrani t-test.
Rezultati. Podnoljivost svih ispitivanih farmaceutskih oblika nimesulida bila je odlina. Kod standardnih tableta, u poreenju sa suspenzijom, ili tableta koje se tope
u ustima, u poreenju sa standardnim tabletama, izraunati intervali poverenja za
relativne razlike logaritamski transformisanih vrednosti maksimalnih koncentracija i
povrina ispod krive bili su van definisanih, i struno prihvaenih granica. Poreenje bitnih farmakokinetikih parametara za tablete koje se tope u ustima i suspenziju ukazalo je na statistiki znaajne razlike meu vrednostima maksimalnih koncentracija (supra bioloka raspoloivost tableta koje se tope u ustima), dok je kritina vrednost odnosa geometrijskih sredina niza logaritamski transformisanih vrednosti povrina ispod krive iznosila 0,945, a odgovarajui 90% interval poverenja
kretao se u rasponu od 0,902 do 0,991. Pri nivou znaajnosti od 5%, primenom
neparametrijskog Wilcoxonovog testa suma rangova, meu ispitivanim farmaceutskim oblicima nimesulida nisu ustanovljene razlike u vremenima potrebnim da se
dostigne maksimalna koncentracija leka u krvi. Zakljuak. Analiza dobijenih rezultata pokazala je da je jedino 90% interval poverenja za relativne razlike logaritamski transformisanih vrednosti povrina ispod krive nimesulida apsorbovanog iz tableta koje se tope u ustima, u poreenju sa suspenzijom, bio ukljuen u raspon
80125%, koji prihvata Agencija za hranu i lekove SAD. Stoga je donet zakljuak
da su samo tablete koje se tope u ustima (Nimulid-MD), cenei ukupnu koliinu
leka koja je dospela u sistemsku cirkulaciju, bioloki ekvivalentne formulaciji koja,
po definiciji, ima apsolutnu bioloku iskoristljivost (Nimulid suspenzija). Pod navedenim uslovima ne mogu se oekivati promene u terapijskoj efikasnosti tokom
prevoenja bolesnika sa jednog na drugi farmaceutski oblik nimesulida.
K lj u n e r e i :

antiinflamatorici, nesteroidni; lekovi, oblici; lekovi,


odnos doza reakcija; farmakokinetika;
bioraspoloivost; terapijska ekvivalentnost.

Correspondence to: Duan Jovanovi, Military Medical Academy, National Poison Control Centre, Crnotravska 17, 11040
Belgrade, Serbia & Montenegro; Phone: +381 11 36 72 579; Fax: +381 11 36 72 187; Cellular: +381 63 25 48 49, E-mail:
NCKTVMA@EUnet.yu