Bioequivalence Studies
In vivo Bioequivalence of Oral Antidiabetic
Agents: Pioglitazone Tablets
Hong Wong a, Yildiz Ozalp b, Audrey Lainessea, and Recep Serdar Alpan b
SFBC Anapharm a, Sainte-Foy, Quebec (Canada), and EIS Eczacıbaşı İlaç Sanayi ve Ticaret A.S.b, Istanbul (Turkey)
Key words
䊏 CAS 112529-15-4
䊏 Pioglitazone, bioequivalence,
clinical pharmacokinetics
Arzneim.-Forsch./Drug Res.
54, No. 9a, 618−624 (2004)
Zusammenfassung
In-vivo-Bioäquivalenz oraler Antidiabe-
tika: Pioglitazon-Tabletten
In der vorliegenden Studie sollte die
Bioverfügbarkeit von zwei Pioglitazon
(CAS 112529-15-4)-Zubereitungen unter-
sucht werden. Dazu wurde eine Bioäqui-
valenzprüfung an 26 gesunden männ-
lichen Probanden durchgeführt, denen
30 mg Pioglitazon-enthaltende Tabletten
618 Wong et al. − Pioglitazone
Summary
The study was designed to evaluate the
bioequivalence of two pioglitazone (CAS
112529-15-4) formulations. The trial was
performed in 26 healthy male volunteers
with the aim of comparing a new generic
product (tablets containing 30 mg pioglit-
azone hydrochloride, test) with the ori-
ginator product (reference). The trial was
performed according to an open, cross-
over design in one study centre. In each
of the two study periods (separated by a
wash-out of 14 days) a single oral dose of
30 mg (test or reference) formulation
was administered. Blood samples were
taken up to 120 h post dose, the plasma
was separated and the concentrations of
pioglitazone and its principal active me-
tabolite hydroxypioglitazone were deter-
mined by LC-MS-MS method. AUC0-inf,
AUC0-t, Cmax and Tmax were calculated for
both formulations.
The mean Cmax of pioglitazone ranged
between 1.01 µg/mL and 1.05 µg/mL,
while the mean AUC0-inf and AUC0-t
ranged between 10.89 µg · h/mL and
10.98 µg · h/mL as well as between 10.56
der Testzubereitung und der Referenzzu-
bereitung oral appliziert wurden. Die Prü-
fung war als offene, randomisierte, Cross-
over-Prüfung in einem Studienzentrum
angelegt. Blutentnahmen erfolgten bis zu
120 h nach der Applikation. Im abge-
trennten Plasma wurde die Bestimmung
von Pioglitazon und Hydroxypioglitazon
(aktiver Metabolit) mittels HPLC-MS-MS
vorgenommen. Die Parameter AUC0-inf,
Arzneim.-Forsch./Drug Res. 54, No. 9a, 618−624 (2004)
µg · h/mL and 10.62 µg · h/mL for the
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test and reference formulations, respec-
tively. The median Tmax for the test tab-
lets was 1.50 h and for the reference was
1.75 h. The ratios test/reference formula-
tion for AUC0-inf, AUC0-t and Cmax were
99.70 %, 100.13 % and 99.17 %, respec-
tively. Furthermore, the 90 % geometric
confidence intervals of the mean ratio of
ln-transformed AUC0-inf were narrow and
symmetrical around 100 %, i.e. 90.59 %
to 109.72 %, for AUC0-t 90.69 % to
110.55 %, whereas for Cmax they were
87.52 % to 112.37 %. As in the case of pi-
oglitazone, mean values of the principal
bioequivalence parameters of hydroxypi-
oglitazone did not differ significantly
after administration of the test and refer-
ence formulations.
In the light of the present study it can
be concluded that the two evaluated piog-
litazone formulations, i.e. test formula-
tion of pioglitazone hydrochloride and
reference formulation, are bioequivalent
in terms of the rate and extent of absorp-
tion.
AUC0-t, Cmax und Tmax wurden für beide
Zubereitungen berechnet. Cmax für die Te-
st- bzw. Referenzzubereitung betrug im
Mittel 1,01 µg/mL bzw. 1,05 µg/mL, für
die AUC0-t 10,56 µg · h/mL bzw. 10,62
µg · h/mL. Der Mittelwert der AUC0-inf be-
trug 10,89 µg · h/mL (Test) bzw. 10,98
µg · h/mL (Referenz). Bis zum Erreichen
maximaler Plasmaspiegel (tmax, Median-
wert) vergingen 1,50 h (Test) bzw.
 Bioequivalence Studies

1,75 h (Referenz). Das mittlere Verhältnis
Test/Referenz lag bei 99.70 % (AUC0-inf ),
100.13 % (AUC0-t) bzw. 99.17 % (Cmax)
Die 90 %-Konfidenzintervalle für die
mittleren Verhältnisse der logarithmier-
ten Zielparameter waren eng und symme-
trisch um 100 % (90,59 %−109,72 % für
AUC0-inf; 90,69 %−110,55 % für AUC0-t;
87.52 %−112.37 % für Cmax). Wie für Pio- die Testzubereitung der Referenzuberei-
glitazon selbst waren die Mittelwerte der tung bioäquivalent ist.
Bioäquivalenzparameter für Hydroxypio-
glitazon nach Applikation der Test- und
der Referenzzubereitung nicht signifi-
kant voneinander verschieden. Auf der
Grundlage der vorliegenden Ergebnisse
kann der Schluß gezogen werden, daβ

Schlüsselwörter: CAS 112529-15-4 · Pioglitazon, Bioäquivalenz, klinische Pharmakokinetik

Özet

Pioglitazon hidroklorür aktif maddesi içe-
ren iki tablet formülasyonu ile yapılan in
vivo biyoeşdeğerlik çalışması
Bu klinik çalışma pioglitazon (CAS
112529-15-4) içeren iki tablet formülasyo-
nunun karşılaştırılması amacıyla 26
kadın ve erkek sağlıklı gönüllüde, her gö-
nüllüye aç karnına, tek doz 30 mg piogli-
trasyonları LC/MS/MS metodu ile öl-
çüldü. AUC0-inf, AUC0-t, Cmax ve Tmax her
iki formülasyon içinde hesaplandı. Piogli-
tazonun ortalama Cmax değeri 1.01 µg/
mL ile 1.05 µg/mL arasında iken, orta-
lama AUC0-inf ve AUC0-t test ve referans
ilaçlar için sırasıyla 10.89 ng · h/ml ile
10.98 ng · h/ml ve 10.56 ng . h/ml ile
10.62 ng · h/ml arasındaydı. Test ve refe-
güven aralıkları dardı ve % 100 civarında
simetrikti. Sözkonusu güvenlik aralıkları
AUC0-inf için % 90.59 ile % 109.72, AUC0-t
için % 90.69 ile % 110.55 arasında iken
Cmax için % 87.52 ile %112.37 arasın-
daydı. Pioglitazon ile birlikte değerlendi-
rilen aktif metaboliti hidroksipioglitazo-
nun biyoeşdeğerlilik göstergelerinin test
ve referans ürün karşılaştırmasında an-

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tazon tablet verilerek; açık, tek merkezli,
randomize, çapraz tasarımlı ve arasında
14 günlük temizlenme dönemi olacak şe-
kilde iki periyodlu, olarak yapıldı. Kan ör-
nekleri oral dozu takip eden 120 saatlik
aralık içinde alındı ve plazmaları ayrıldık-
tan sonra pioglitazon ve onun aktif meta-
boliti hidroksipioglitazon plazma konsan-
rans tabletleri için medyan Tmax sırasıyla
1.50 saat ve 1.75 saatti. Test formülasyon-
larının ortalamalarının referans formü-
lasyon ortalamalarına olan oranları
AUC0-inf, AUC0-t ve Cmax için sırasıyla
% 99.70, % 100.13 ve % 99.17’ydi. Ayrıca,
AUC0-inf (ln-transformed) ve AUC0-t nin
ortalama oranlarının % 90’lik geometrik
lamlı değişiklikler göstermediği saptandı.
Mevcut çalışmanın ışığında, değerlendiri-
len iki piyoglitazon formülasyonunun
(test ve referans) emilim hızı ve kana ge-
çen miktar anlamında biyoeşdeğer oldu-
kları sonucuna varıldı.

Anahtar kelimeler: CAS 112529-15-4 · Pioglitazon, biyoeşdeğerlik, klinik farmakokinetik

1. Introduction pared with placebo, pioglitazone significantly reduced

Pioglitazone (CAS 112529-15-4) is an orally adminis-
tered insulin sensitising thiazolidinedione agent that
has been developed for the treatment of type 2 diabetes
mellitus. Pioglitazone activates the nuclear peroxisome
proliferator activated receptor-γ (PPAR-γ), which leads
to the increased transcription of various proteins regu-
lating glucose and lipid metabolism [1]. These proteins
amplify the post-receptor actions of insulin in the liver
and peripheral tissues, which leads to improved glyca-
emic control with no increase in the endogenous secre-
tion of insulin. Studies show that pioglitazone stimu-
lates the uptake of glucose and fatty acids into cells by
promoting the synthesis and expression of cellular glu-
cose and fatty acid transporters [2, 3]. In placebo-con-
trolled clinical studies, pioglitazone, whether used as
monotherapy or in combination with sulphonylurea,
metformin or insulin, effectively improved glycaemic
control in patients with type 2 diabetes as evidenced
by significant reductions in HbA1c and fasting plasma
glucose. Pioglitazone also had a beneficial effect on the
abnormal lipid profile seen in type 2 diabetes. Com-
serum triglycerides and increased high density lipo-
protein cholesterol with no change in low density lipo-
protein or total cholesterol [4].
In humans pioglitazone undergoes extensive metab-
olism, yielding primarily keto- (M-III) and hydroxy- (M-
IV) derivatives of pioglitazone. These two active metab-
olites mainly contribute to the extended glucose-lower-
ing effects. The hepatic metabolism of pioglitazone is
catalysed mainly by CYP2C8 and CYP3A [5]. However,
unlike troglitazone, studies have provided no evidence
to suggest that pioglitazone administration leads to in-
hibition or induction of any of the P450 isoenzymes in-
volved in drug metabolism. Therefore pioglitazone may
have a lower potential for drug interaction. In patients
with renal impairment a decrease in AUC of pioglita-
zone and its major metabolites MIII and MIV was ob-
served with increasing kidney failure. This suggests in-
creased hepatic clearance of the drug secondary to re-
duced protein binding in plasma, with no net change
in free plasma drug concentrations [6].

Arzneim.-Forsch./Drug Res. 54, No. 9a, 618−624 (2004)

Wong et al. − Pioglitazone 619
Bioequivalence Studies
The present paper describes the results of a bioequi-
valence trial of two pioglitazone formulations, i.e. a new
pioglitazone hydrochloride generic product as the test
formulation and an orginator product used as the refer-
ence formulation.
2. Methods
2.1. Subjects
Twenty-six healthy, adult, non-smoking male volunteers, aged
between 18 and 55 years, participated in this single-center,
single-dose, randomised, open-label, two-way cross-over bio-
equivalence study conducted at Anapharm Inc. (Sainte-Foy,
Quebec, Canada). All subjects met the inclusion and exclusion
criteria described in the protocol and were judged eligible for
the study, based on medical history, demographic data, med-
ication history, physical examination, vital signs and clinical
laboratory tests. The study was conducted in accordance with
internationally-accepted standards of Good Clinical Practices,
Good Laboratory Practices, local regulatory requirements, and
the principles of the Declaration of Helsinki (Edinburgh, Scot-
land, 2000).
2.2. Pharmacokinetic study
Each subject received either Treatment A [pioglitazone hydro-
chloride 30 mg tablet, manufactured by Eczacıbaşı Pharmaceu-
ticals, Istanbul, Turkey (test)] or Treatment B [30 mg tablet (ref-
erence)] after a supervised overnight fasting of at least 10 h, in
accordance with the randomisation schedule, with a wash-out
period of 14 days between doses.
During each study period, blood samples were taken from
each subject pre-dose and at 0.5, 1.0, 1.5, 1.75, 2.0, 2.5, 3.0, 3.5,
4.0, 4.5, 5.0, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0, 36.0, 48.0, 72.0, 96.0
and 120 h post-dose (n = 23). Plasma was obtained from each
blood sample and stored in a −80 °C (−65 °C to −85 °C) freezer,
pending assay for pioglitazone and hydroxypioglitazone (M-IV)
plasma concentrations.
2.3. Analytical method
Plasma concentrations of pioglitazone and hyroxy-pioglitazone
were measured by a sensitive and specific LC/MS/MS method.
Analysis was perfomed on a PE SCIEX API 4000 (Perkin Elmer,
Toronto, Canada). Positive ions were measured using MRM
(Multiple Reaction Monitoring) mode with m/z 357.1 → 135.1
for pioglitazone and 373.1 → 150.1 for hydroxy-pioglitazone.
The lower limit of quantitation for pioglitazone and hydroxy-
pioglitazone were 10.12 ng/mL and 0.99 ng/mL, respectively.
The standard curve ranges of the plasma concentrations for
pioglitazone and hydroxy-pioglitazone were 10.12 ng/mL to
1517.40 ng/mL and 0.99 ng/mL to 742.05 ng/mL, respectively.
Pioglitazone and hydroxy-pioglitazone were extracted from
plasma by using liquid-liquid phase extraction. Chromato-
graphic conditions: The mobile phase used was a mixture of
methaol/ammonium acetate in a 1/1 ratio. The reverse phase
chromatography was performed on a Zorbax SB-C18 (2), 75 ×
4.6 mm, 3.5 µm (CS, Brockville, Canada), with a flow rate of 1
mL/min and an injection volume of 20 µL. The chromato-
graphic run time lasted 4.5 min and linearity over the calibra-
tion range was 0.9971 for both analytes. The between-run accu-
racy ranged from 90.20 % to 100.65 % for pioglitazone with pre-
cision ranged from 3.33 % to 4.34 %. For hydroxy-pioglitazone,
620 Wong et al. − Pioglitazone
the between-run accuracy ranged from 90.52 % to 96.53 % with
precision ranged from 2.61 % to 4.35 %. The within-run accu-
racy for pioglitazone ranged from 87.83 % to 96.57 % with pre-
cision ranging form 1.47 % to 6.91 %. For hydroxy-pioglitazone,
the within-run accuracy ranged from 87.80 to 96.33 % with pre-
cision ranging form 0.96 to 5.78 %. The method has been
shown to be accurate and repoducible and was successfully
applied for the analysis of clinical samples.
2.4. Pharmacokinetic analysis
Pharmacokinetic parameters, for both pioglitazone and
hydroxypioglitazone, were obtained using non-compartmental
methods. Cmax, the maximum observed concentration, and
Tmax, the time to reach that peak concentration, were deter-
mined for each subject and for each treatment. AUC0-t, the area
under the plasma concentration-time curve from time zero to
the time of the last non-zero concentration was calculated us-
ing the linear trapezoidal rule. The AUC0-inf, the area under the
concentration-time curve from time zero to infinity (extrapo-
lated) was calculated as: AUC0-t + Ct/Kel, where: Ct = the last
non-zero concentration. The residual area, the percentage of
extrapolated area under the curve, was calculated as: 100*(1-
AUC0-t/AUC0-inf ). To calculate the elimination rate constant
(Kel), regression analyses were performed on the natural log
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(ln) of plasma concentration values (y) versus time (x). The Kel
was taken as the slope multiplied by (−1) and the apparent
half-life (T1/2 el) as (ln 2)/Kel.
2.5. Statistical analysis
Using General Linear Models procedure (GLM, SAS Institute,
Cary, NC, USA), ANOVA was performed on Kel and T1/2 el and
on ln-transformed AUC0-t, AUC0-inf and Cmax at the alpha level
of 0.05. The model included sequence, subject within se-
quence, period and treatment as factors. A non-parametric
test, the Wilcoxon’s test was carried out to compare the Tmax
between treatments. Ratio of means test/reference (Treatment
A/Treatment B) and 90 % geometric confidence interval for the
ratio of means, based on the least-squares means from the
ANOVA of the ln-transformed data, were calculated for AUC0-t,
AUC0-inf and Cmax.
3. Results
3.1. Pharmacokinetic study
All 26 subjects who were enrolled completed the study.
In accordance with the study protocol, plasma samples
of the first 24 subjects completing the study were ana-
lysed and used for pharmacokinetic and statistical anal-
yses. The plots of the mean plasma pioglitazone and
hydroxypioglitazone levels over 120-h sampling period
for both untransformed and ln-transformed data are
presented in Fig. 1 and in Fig. 2. At it is observed in
these figures, the plasma concentrations of pioglitazone
and its main metabolite hydroxypioglitazone did not
differ significantly after administration of both formula-
tions, i.e. pioglitazone test and reference tablets.
Table 1 summarises the pharmacokinetic parameters
of pioglitazone in 24 fasted healthy male subjects who
received a single dose of the two pioglitazone formula-
tions in two different occasions, separated by a washout
Arzneim.-Forsch./Drug Res. 54, No. 9a, 618−624 (2004)
 Bioequivalence Studies

C [ng/mL]
1200

1000

800

600

400

200

0
0.0 6.0 12.0 18.0 24.0 30.0 36.0 42.0 48.0 54.0 60.0 66.0 72.0
Time (h)
lnC (ng/mL)
8.00

7.00

6.00

5.00

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4.00

3.00

2.00

1.00

0.00
0.0 6.0 12.0 18.0 24.0 30.0 36.0 42.0 48.0 54.0 60.0 66.0 72.0
Time (h)

Fig. 1: Top: Mean concentration-time curves of pioglitazone after administration of the test (pioglitazone hydrochloride, 30 mg) (䊐)
and reference formulations (originator product, 30 mg) (+). Bottom: Mean ln-transformed concentration-time curves of pioglitazone
after administration of the test (pioglitazone hydrochloride, 30mg) (䊐) and reference formulations (originator product, 30 mg) (+).

period of 14 days. The mean Cmax were 1015.46 ng/mL
and 1051.75 ng/mL, while the mean AUC0-inf were
10887.82 ng · h/mL and 10984.58 ng · h/mL for the test
and reference formulations, respectively. The mean
AUC0-t were 10560.15 ng · h/mL and 10619.09 ng · h/
mL for the test and reference formula, respectively. The
median Tmax was 1.50 h for the test tablet and 1.75 h
for the reference formula. The mean T1/2 el was 10.71 h
for the test formulation and 9.96 h for the reference
formulation. Mean Kel values for the test and reference

Table 2: Pharmacokinetic parameters (means ± SD) of hydroxy-

Table 1: Pharmacokinetic parameters (mean ± SD) of pioglitazone
pioglitazone after a single 30 mg oral dose of pioglitazone hy-
after a single 30 mg oral dose of pioglitazone hydrochloride to 24
drochloride to 24 healthy male volunteers under fasting condi-
healthy male volunteers under fasting conditions.
tions.
Parameter (unit) Test Reference Parameter (unit) Test Reference
AUC0-t (ng · h/mL) 10560.15 ± 3001.05 10619.09 ± 2971.27 AUC0-t (ng · h/mL) 21651.75 ± 5984.51 21961.09 ± 6246.84
AUC0-inf (ng · h/mL) 10887.82 ± 3042.26 10984.58 ± 3011.16 AUC0-inf (ng · h/mL) 22592.14 ± 6486.82 22912.12 ± 6819.22
Cmax (ng/mL) 1015.46 ± 238.15 1051.75 ± 351.89 Cmax (ng/mL) 404.75 ± 102.29 410.21 ± 115.38
Residual area (%) 3.11 ± 2.29 3.53 ± 2.04 Residual area (%) 3.93 ± 1.41 3.91 ± 1.71
Tmax (h)a) 1.50 ± 1.13 1.75 ± 0.75 Tmax (h)a) 16.0 ± 4.0 14.0 ± 6.0
Kel (h-1) 0.0764 ± 0.0272 0.0811 ± 0.0278 Kel (h-1) 0.0300 ± 0.0033 0.0303 ± 0.0039
T1/2 el (h) 10.71 ± 5.27 9.96 ± 4.78 T1/2 el (h) 23.40 ± 2.72 23.24 ± 3.28
AUC0-t = the area under the plasma concentration-time curve AUC0-t = the area under the plasma concentration-time curve
from time zero to the time of the last non-zero concentration, from time zero to the time of the last non-zero concentration,
AUC0-inf = the area under the concentration-time curve from time AUC0-inf = the area under the concentration-time curve from time
zero to infinity, Cmax = the maximum observed concentration, Resi- zero to infinity, Cmax = the maximum observed concentration, Resi-
dual area = the percentage of extrapolated area under the curve dual area = the percentage of extrapolated area under the curve
calculated as: 100 · (1 − AUC0-t/AUC0-inf ), Tmax = the time to reach calculated as: 100 · (1 − AUC0-t/AUC0-inf ), Tmax = the time to reach
that peak concentration, Kel = the elimination rate constant, T1/2 that peak concentration, Kel = the elimination rate constant, T1/2
el = the elimination rate constant. el = the elimination rate constant.
a) a)
For Tmax, medians and interquartile ranges are presented instead For Tmax, medians and interquartile ranges are presented instead
of means and SD. of means and SD.

Arzneim.-Forsch./Drug Res. 54, No. 9a, 618−624 (2004)

Wong et al. − Pioglitazone 621
Bioequivalence Studies

C (ng/mL)
450

400

350

300

250

200

150

100

50

0
0 10 20 30 40 50 60 70 80 90 100 110 120
Time (h)
lnC (ng/mL)
7.00

6.00

5.00

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4.00

3.00

2.00

1.00

0.00
0 10 20 30 40 50 60 70 80 90 100 110 120
Time (h)

Fig. 2: Top: Mean concentration-time curves of hydroxypioglitazone after administration of the test (Pioglitazone hydrochloride, 30
mg) (䊐) and reference formulations (originator product, 30 mg) (+). Bottom: Mean ln-transformed concentration-time curves of
hydroxypioglitazone after administration of the test (Pioglitazone hydrochloride, 30 mg) (䊐) and reference formulations (originator
product, 30 mg) (+).

formulations were 0.0764 h-1 and 0.0811 h-1, respec-
tively.
The same pharmacokinetic parameters for hydroxy-
pioglitazone are presented in Table 2. The mean Cmax
were 404.75 ng/mL and 410.21 ng/mL, while the mean
AUC0-inf were 22592.14 ng · h/mL and 22912.12 ng · h/
mL for the test and reference formulations, respectively.
The mean AUC0-t were 21651.75 ng · h/mL and 21961.09
ng · h/mL for the test and reference formula, respec-
tively. The median Tmax were 16.0 h and 14.0 h for the
test and reference formulations, respectively. The mean
T1/2 el was 23.40 h for the test formulation and 23.24 h
for the reference formulation. Mean Kel values for the
test and reference tablet were 0.0300 h-1 and 0.0303 h-1, re-
spectively. For both pioglitazone and hydroxypioglita-
zone the mean residual areas were lower than 20 %.

Table 4: Hydroxypioglitazone ratios of least-squares means and

Table 3: Pioglitazone ratios of least-squares means and the 90 % the 90 % geometric confidence intervals (CI) based on the pair-
geometric confidence intervals (CI) based on the pairwise com- wise comparisons of the ln-transformed AUC0-t, AUC0-inf and
parisons of the ln-transformed AUC0-t, AUC0-inf and Cmax. Cmax.
AUC0-t AUC0-inf Cmax AUC0-t AUC0-inf Cmax
a)
Ratio 100.13 99.70 99.17 Ratioa)
98.87 98.89 99.61
90 % Geom. CI (%)b) 90.69 to 110.55 90.59 to 109.72 87.52 to 112.37 90 % Geom. CI (%) b) 91.35 to 107.01 91.28 to 107.13 91.25 to 108.72
Intra-subject CV (%) 20.18 19.51 25.61 Intra-subject CV (%) 16.05 16.29 17.81
a) a)
Calculated using least-squares means according to the formula: Calculated using least-squares means according to the formula:
e(test-reference) × 100. e(test-reference) × 100.
b) b)
90 % Geometric confidence interval using ln-transformed data. 90 % Geometric confidence interval using ln-transformed data.
CV = coefficient of variation. CV = coefficient of variation.

Arzneim.-Forsch./Drug Res. 54, No. 9a, 618−624 (2004)

622 Wong et al. − Pioglitazone

ANOVA did not detect any statistically significant dif-
ference between treatments for ln-transformed AUC0-t,
AUC0-inf and Cmax, and untransformed T 1/2el and Kel for
both pioglitazone and hydroxy-pioglitazone. Moreover,
Wilcoxon’s test did not detect any statistically signifi-
cant difference between treatments for untransformed
Tmax for both pioglitazone and hydroxypioglitazone.
The mean ratios as well as the 90 % geometric con-
fidence intervals of the mean ratio of ln-transformed
AUC0-t, AUC0-inf and Cmax of the test and reference for-
mulation for pioglitazone and for hydroxypioglitazone
are displayed in Table 3 and Table 4, respectively. In
accordance with the study protocol, the hypothesis of
bioequivalence of the formulations was accepted if the
90 % confidence intervals of the mean ratio of the test
to reference products were within the acceptance range
of 80 % to 125 % for ln-transformed AUC0-t and within
the acceptance range of 75 % to 133 % for ln-trans-
formed Cmax for both pioglitazone and hydroxypioglita-
zone. This was evidently true for pioglitazone [test
product vs. reference product: (90.59 % to 109.72 %)] for
AUC0-inf, [test product vs. reference product: (90.69 % to
110.55 %)] for AUC0-t and even met the more restrictive
requirement of 80 % to 125 % [test product vs. reference
product: (87.52 % to 112.37 %)] for Cmax. Bioequivalence
was also demonstrated with hydroxypioglitazone [test
product vs. reference product: (91.28 % to 107.13 %)] for
AUC0-inf, [test product vs. reference product: (91.35 % to
107.01 %)] for AUC0-t and even met the more restrictive
requirement of 80 % to 125 % [test product vs. reference
product: (91.25 % to 108.72 %)] for Cmax. The pioglita-
zone intra-subject CVs for AUC0-t, AUC0-inf and Cmax
were respectively 20.18 %, 19.51 % and 25.61 %. The
hydroxypioglitazone intra-subject CVs for AUC0-t, AUC0-
inf and Cmax were respectively 16.05 %, 16.26 % and
17.81 %.
3.2. Drug tolerance
During the study, adverse events were mild or moderate
in severity and no serious, severe or significant adverse
events were reported. The laboratory screening pre-
sented no signs of adverse events or adverse drug reac-
tions. Subjects were monitored for adverse events as
specified in the protocol. A total of 38 post-dose adverse
events were recorded: 12 following administration of
the test product, 24 following administration of the ref-
erence product, and 2 associated with clinically signifi-
cant post-study laboratory results (exact onset time and
date unknown). All adverse events were followed by
complete restitution within a short time period. Thus,
the products were well tolerated overall.
4. Discussion
Pioglitazone is a thiazolidinedione that increases insu-
lin sensitivity in target tissues. It is well-absorbed, with
a mean absolute bioavailability of 83 % and reaching
maximum concentrations in around 1.5 h. It is metab-
olised by the hepatic cytochrome P450 enzyme system
with the formation of two principal active metabolites,
i.e. keto- (M-III) and hydroxy- (M-IV) derivatives of pi-
oglitazone. The half-life of the drug is about 9 h, but
Arzneim.-Forsch./Drug Res. 54, No. 9a, 618−624 (2004)
Bioequivalence Studies
the two active metabolites mainly contribute to the ex-
tended glucose-lowering effects [7].
The aim of the present study was to evaluate the
bioavailability of the tested pioglitazone hydrochloride
30 mg tablet manufactured by Eczacıbaşı Pharmaceu-
ticals and a reference pioglitazone 30 mg tablets admin-
istered as a single oral dose.
The mean residual area for pioglitazone and
hydroxypioglitazone lower than 20 % for both evaluated
formulations indicated that both the duration of sam-
pling time and the sensitivity of the analytical method
were sufficient. The plots of the mean pioglitazone and
its main metabolite − hydroxypioglitazone did not differ
significantly, indicating comparative pharmacokinetic
profile of the two evaluated drug formulations.
For the parent compound, i.e. pioglitazone, the mean
Cmax were 1015.46 ng/mL and 1051.75 ng/mL, while the
mean AUC0-t were 10560.15 ng · h/mL for the test tab-
lets and 10619.09 ng · h/mL for the reference formula-
tion. The results of the present trial regarding pharma-
cokinetics parameters correspond to published data [4,
7, 9]. A median time to maximum serum concentration
of 1.5 h was reported (range 0.5 to 3.0 h), which was not
influenced by an administered dose of the drug from 2
Downloaded by: NYU. Copyrighted material.
to 60 mg. For both single and multiple doses, both the
maximum serum concentration and the area under the
curve of pioglitazone serum concentration against time
increased linearly with increasing dose.
Pioglitazone is an enantiomeric parent drug given as
a racemate. The ratio of the enantiomers in human
plasma is 1:1 [7]. This information and the fact that pi-
oglitazone exhibits linear kinetic behavior was taken
into account when planning the current trial. It was
therefore decided that no enantioselective analytical
method will be needed.
As for the secondary bioequivalence parameter Tmax,
the median values of the two analysed pioglitazone for-
mulas were comparable, i.e. 1.50 for the test tablet and
1.75 h for reference one. These observations testify that
the two pioglitazone formulations are very similar in
terms of the rate of absorption. Furthermore, the sim-
ilar values of T1/2 el and Kel of the evaluated tablets in-
dicate comparable rate of pioglitazone elimination from
the body.
Since hydroxypioglitazone is an active metabolite of
pioglitazone [4, 7], its kinetics was also evaluated. Ac-
cording to the currently valid CPMP Note for Guidance
for the Evaluation of Bioavailability and Bioequivalence,
the evaluation of hydroxypioglitazone would not have
been absolutely necessary due to the linear kinetics of
pioglitazone. The results of the present trial demon-
strate that the 90 % confidence intervals for the metab-
olite were narrower and the intra-individual CV’s were
lower compared to those of the parent compound. It
can be thus concluded that in the case of pioglitazone,
the parent compound is more appropriate for the
evaluation of bioequivalence and a simultaneous evalu-
ation of the metabolite is not absolutely necessary.
Based on the results of the present studies it can be
concluded that the two pioglitazone formulations, i.e.
the test formulation manufactured by Eczacıbaşı Phar-
maceuticals and the reference preparation, are bioequi-
valent.
Wong et al. − Pioglitazone 623
Bioequivalence Studies

5. References [7] Hanefeld, M. Pharmacokinetics and clinical efficacy of

pioglitazone. Int. J. Clin. Pract. Suppl. 121, 19 (2001)
[1] Lehmann, J., Moore, L., Smith-Oliver, T. et al., An antidia-
[8] CPMP Note for guidance: Investigation of bioavailability
betic thiazolidinedione is a high affinity ligand for peroxisome
and bioequivalence. CPMP/EWP/QWP/1401/98 (1998)
proliferator-activated receptor γ (PPAR γ). J. Biol. Chem. 270,
[9] Eckland, D., Danhoh, M., Clinical pharmacokinetics of
12953 (1995)
pioglitazone. Exp. Clin. Endocrinol. Diabetes. 108 (Suppl. 2),
[2] Sandouk, T., Reda, D., Hofman, C., The antidiabetic agent
S234 (2000)
pioglitazone increases expression of glucose transporters in
3T3-F442A cells by increasing messenger ribonucleic acid tran-
script stability. Endocrinology 133, 352 (1993)
[3] Motojima, K., Passilly, P., Peters, J., Expression of putative
fatty acid transporter genes are regulated by peroxisome pro-
liferator-activated receptor α and γ activators in a tissue- and
Correspondence:
inducer specific manner. J. Biol. Chem. 273, 16710 (1998)
Recep Serdar Alpan, MD, PhD, MSc,
[4] Gillies, P., Dunn, Ch,. Pioglitazone. Drugs 60, 333 (2000)
[5] Nowak, S., Edwards, D., Clarke, A., et. al., Pioglitazone: Eczacıbaşı Pharmaceuticals,
effect on CYP3A4 activity. J. Clin. Pharmacol. 42, 1299 (2002) Büyükdere Caddesi, Ali Kaya Sk. No: 7,
[6] Edwards, G., Eckland, D., Pharmacokinetics of pioglita- Levent, 34394, Istanbul (Turkey)
zone in patients with renal impairment. Diabetologia 48 Fax: +90 212 3508650
(Suppl. 1), A230 (1999) [abstract] E-mail: serdara@eczacibasi.com.tr

Downloaded by: NYU. Copyrighted material.

Bioequivalence Study of Rofecoxib
Tablets
Rossen Koytchev a, Yildiz Ozalp b, Aydin Erenmemisogluc, Mike John van der Meer d, and Recep Serdar Alpan b

Cooperative Clinical Drug Research and Development a, Neuenhagen (Germany), EIS Eczacıbaşı
İlaç Sanayi ve Ticaret A.S.b, Istanbul (Turkey), Erciyes University School of Medicinec, Kayseri (Turkey),
and Trident Bioanalytics Ltd.d, Cork (Ireland)

Summary

Key words
䊏 CAS 162011-90-7
䊏 Ecrox
䊏 Rofecoxib, bioequivalence,
clinical pharmacokinetics
Arzneim.-Forsch./Drug Res.
54, No. 9a, 624−628 (2004)
The study was designed to evaluate the
bioavailability of two rofecoxib (CAS
162011-90-7) tablet formulations.
Twenty-four healthy male volunteers
were administered a 25 mg tablet of the
test formulation (Ecrox) containing ro-
fecoxib or the originator product (refer-
ence). The trial was performed according
to an open, cross-over design with a
wash-out period of 7 days. Blood
samples were taken up to 72 h post dose,
the plasma was separated and the con-
centrations of rofecoxib were determined
by an HPLC method. The mean Cmax
were 192.07 ng/mL and 187.35 ng/mL,
while the mean AUC0-t were 3613.84 ng ·
h/mL and 3501.56 ng · h/mL for the test
and reference formulations, respectively.
The median tmax was 3.75 h for the test
tablet and 4.00 h for the reference formu-
lation. The mean t1/2 el was 10.66 h and
10.61 h for the test and reference formu-
lation, respectively. Mean MRT values for
the test and reference tablets were
15.34 h and 15.33 h, respectively. No sig-
nificant differences of pharmacokinetic

Arzneim.-Forsch./Drug Res. 54, No. 9a, 624−628 (2004)

624 Koytchev et al. − Rofecoxib
PROTOKOL UJI BIOEKIVALENSI
SEDIAAN ORAL LEPAS CEPAT
PIOGLITAZONE HCL
Praktikum Biofarmasi Farmakokinetika II

F-9:
FELITA SUSANTO/110117071
NICOLE GERALDINE C./110117074
REZA AZIZUL H./110117250
1. Latar Belakang

Pioglitazone 5-((4-(2-(5-ethyl-2-pyridinyl)ethoxy)phenyl)methyl)-2,4-
thiazolidinedione, mempunyai rumus empiris C19H20N2O3S, dan rumus strukturnya
digambarkan sebagai berikut :

Pioglitazone adalah obat antidiabetik golongan tiazolidindion peka insulin yang

diberikan secara oral yang telah dikembangkan untuk pengobatan diabetes mellitus tipe
2. Studi menunjukkan bahwa pioglitazone merangsang pengambilan glukosa dan asam
lemak ke dalam sel dengan mempromosikan sintesis dan ekspresi transpoter glukosa
seluler dan asam lemak. Konsentrasi plasma puncak terjadi dalam 2 jam dan
bioavailabilitas melebihi 80%. Cmax rata-rata pioglitazone berkisar antara 1,01 μg / mL
dan 1,05 μg / mL, sedangkan rata-rata AUC0-~ dan AUC0-t berkisar antara 10,89 μg ·
jam / mL dan 10,98 μg · jam / mL serta antara 10,56 μg · jam / mL dan 10,62 µg · jam
/ mL masing-masing untuk formulasi uji dan referensi. Tmax rata-rata untuk tablet uji
adalah 1,50 jam dan untuk referensi adalah 1,75 jam.

Menurut BPOM, salah satu kriteria obat oral yang perlu diuji bioekivalensi in vivo
adalah obat yang digunakan untuk kondisi yang serius yang memerlukan respons terapi
yang pasti (critical use drugs), yang salah satu contohnya adalah obat oral
hipoglikemik, yang mencakup golongan tiazolidindion. Dengan kata lain, uji
bioekivalensi in vivo ini perlu dilakukan terhadap obat pioglitazone. Oleh sebab itu,
perlu dirancang penelitian untuk mengevaluasi bioekivalensi dari formulasi
pioglitazone generik baru yang ingin diedarkan. Evaluasi bioekivalensi ini dilakukan
 dengan membandingkan biovailabilitas dari formulasi pioglitazone generik baru yang
ingin mendapat izin edar terhadap formulasi pioglitazone inovator.

2. Tujuan Penelitian

Penelitian ini dimaksudkan untuk menguji bioekivalensi tablet Pioglitazone HCl 30 mg

yang diproduksi oleh pabrik Eczacıbas¸ı Pharmaceuticals di Istanbul, Turki terhadap
tablet pioglitazone HCl 30 mg inovator (Actos ®).

a. Tujuan umum : Untuk menjamin efikasi, keamanan dan mutu tablet Pioglitazone
HCl 30 mg yang diproduksi oleh pabrik Eczacıbas¸ı Pharmaceuticals di Istanbul,
Turki yang beredar.
b. Tujuan khusus : Untuk menjamin obat tablet Pioglitazone HCl 30 mg yang
diproduksi oleh pabrik Eczacıbas¸ı Pharmaceuticals di Istanbul, Turki bioekivalen
dengan obat inovator dan untuk menentukan bioavailabilitas relatif pioglitazone
pada formulasi obat uji untuk uji klinis produk yang akan diedarkan.

3. Rancangan Penelitian
3.1 Penelitian ini dirancang untuk mengevaluasi bioekivalensi tablet Pioglitazone HCl
30 mg uji terhadap tablet pioglitazone HCl 30 mg inovator (Actos ®) sebagai
referensi.
3.2 Penelitian ini dilakukan sesuai dengan standar yang diterima secara internasional
dari Praktik Klinik yang Baik, Praktik Laboratorium yang Baik, persyaratan
peraturan lokal, dan prinsip-prinsip Deklarasi Helsinki (Edinburgh, Skotlandia,
2000).
3.3 Di dalam penelitian ini terdapat 26 subyek yang terdaftar menyelesaikan studi,
dimana 2 subyek merupakan subyek cadangan. Sesuai dengan protokol penelitian,
sampel plasma dari 24 subjek awal yang menyelesaikan penelitian dianalisis dan
digunakan untuk analisis farmakokinetik dan statistik.
3.4 Uji coba dilakukan sesuai dengan desain menyilang acak label terbuka di satu pusat
studi, saat masing-masing dua periode penelitian, dimana per periode penelitian
memerlukan waktu selama 5 hari (dipisahkan oleh periode wash out selama 14
hari), dengan total waktu penelitian selama 24 hari.
 Subyek Produksi Obat
Waktu I Waktu II
1 A B
2 B A
3 A B
4 B A
5 A B
6 B A
7 A B
8 B A
9 A B
10 B A
11 A B
12 B A
Periode Wash
13 A B
out 2 minggu
14 B A
15 A B
16 B A
17 A B
18 B A
19 A B
20 B A
21 A B
22 B A
23 A B
24 B A
25 A B
26 B A

4. Kriteria Pemilihan Subyek

Berjenis kelamin pria, sehat, tidak merokok, berusia antara 18-55 tahun. Subyek
ditentukan memenuhi kriteria protokol melalui penilaian terhadap rekam medis, data
demografi, riwayat pengobatan, tanda vital dan uji laboratorium.

5. Prosedur
5.1 Perlakuan terhadap Subyek
5.1.1 Subyek diminta berkumpul pada pukul 06.00 untuk melaksanakan prosedur
uji. Sebelumnya subyek telah dipuasakan selama 10 jam, dengan kata lain
tidak mengkonsumsi makanan atau minuman selain air putih sejak pukul
22.00 sehari sebelumnya.
5.1.2 Sebelum diberikan obat, sampel darah subyek diambil terlebih dahulu
sebanyak 10,0 mL pada pukul 07.00 (t0). Lalu, pada pukul 07.15 subyek
 diberi 1 tablet pioglitazone HCl uji (Perlakuan A)/referensi (Perlakuan B)
yang diminum bersama air putih. Sampel darah subyek lalu diambil
sebanyak 10,0 mL tiap jam ke 0.5, 1.0, 1.5, 1.75, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5,
5.0, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0, 36.0, 48.0, 72.0, 96.0, dan 120.0 setelah
obat diminumkan.
5.1.3 Sampel darah tersebut diambil bagian plasma dengan mensentrifugasi
darah yang sudah diberi antikoagulan. Plasma yang didapat lalu disimpan
pada freezer dalam suhu -80° C (-65° C s/d -85° C) sampai dilakukan
analisis.
5.1.4 Setelah pemberian obat pertama, dilakukan prosedur yang sama dengan
memberikan obat pembanding setelah periode wash out.
5.1.5 Sarapan dan makan malam yang sudah distandarkan diberikan ke subyek
pada 4 dan 10 jam setelah obat dikonsumsi.
5.2 Detail Bahan Penelitian
5.2.1 Bahan Penelitian
Tablet pioglitazone HCl 30 mg generik diproduksi oleh pabrik Eczacıbas¸ı
Pharmaceuticals di Istanbul, Turki sebagai obat uji dan tablet pioglitazone
HCl 30 mg inovator (Actos ®) sebagai obat referensi.
5.2.2 Jadwal Pengamatan dan Pengumpulan Sampel
Sampel darah diambil 15 menit sebelum subyek meminum obat pada pukul
07.00 (t0) dan pada jam ke 0.5, 1.0, 1.5, 1.75, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0,
6.0, 8.0, 10.0, 12.0, 16.0, 24.0, 36.0, 48.0, 72.0, 96.0, dan 120.0 setelah obat
diminumkan.
Waktu
t (jam) Keterangan
(pukul)
0.0 07.00 Sampel sebelum obat diberikan (10,0 mL)
0.5 07.30
Sampel sebelum Cp max (10,0 mL)
1.0 08.00
1.5 08.30
1.75 08.45 Sampel sekitar Cp max (10,0 mL)
2.0 09.00
2.5 09.30
3.0 10.00
3.5 10.30
4.0 11.00 Sampel setelah Cp max (10,0 mL)
4.5 11.30
5.0 12.00
6.0 13.00
 8.0 15.00
10.0 17.00
12.0 19.00
16.0 23.00
24.0 07.00
36.0 19.00
48.0 07.00
72.0 07.00
96.0 07.00
120.0 07.00

5.3 Efek samping

Fraktur tulang, mati rasa/numbness, gangguan penglihatan, peningkatan berat
badan, edema makular, insomnia, kanker kandung kemih (tidak umum), disfungsi
liver (jarang).

6. Kriteria Pengeluaran Subyek

6.1 Subyek yang hipersensitif dengan pioglitazone
6.2 Subyek dengan riwayat gagal jantung
6.3 Subyek yang sedang/sebelumnya mengidap kanker kandung kemih
6.4 Subyek dengan hematuria tidak terinvestigasi makroskopik

7. Macam Cuplikan Biologik

7.1 Waktu-waktu pengambilan :
Darah: 15 menit sebelum minum obat, jam ke 0,5; 1,0; 1,5; 1,75; 2,0; 2,5; 3,0; 3,5;
4.0; 4.5; 5.0; 6.0; 8.0; 10.0; 12.0; 16.0; 24.0; 36.0; 48.0; 72.0; 96.0 dan 120 setelah
obat diminum.
7.2 Gambaran cara penanganan cuplikan:
7.2.1 Pengambilan darah :
a. Disinfeksi dengan alcohol swab daerah kulit subyek yang akan
disuntik.
b. Pasang ikatan (tourniquet) pada tangan bagian atas subyek.

c. Beri label identitas subjek pada tabung. Untuk preparasi plasma,

dinding dalam tabung diberi antikoagulan.

d. Tegangkan kulit di atas vena subyek dengan jari tangan kiri agar vena
tidak bergeser, kemudian tusuk vena dengan jarum IV canula.
 e. Setelah darah terlihat mengalir dari pembuluh darah vena ke dalam
jarum, tarik jarum keluar, tinggalkan plastik IV canula di dalam
pembuluh darah dan masukkan pelan-pelan sampai batas yang
ditentukan.

f. Masukan syringe ke dalam hub canula kemudian ambil sampel darah

sesuai yang dibutuhkan

g. Tutup IV canula dengan instopper, lalu plester IV canula dengan

micropore.
h. Lepas ikatan tourniquet dari lengan subyek.
i. Catat waktu saat subyek minum obat pada catatan pengambilan darah.

j. Pengambilan berikutnya buka instopper, lalu ulangi poin f hingga h.

k. Beri tanda/paraf catatan pengambilan darah sesuai kolom waktunya

setiap selesai melakukan pengambilan darah.

7.2.2 Penanganan darah :

a. Sampel darah diambil bagian plasma dengan cara mensentrifugasi
darah yang sudah diberi antikoagulan.
b. Konsentrasi plasma pioglitazone dan hidroksi-pioglitazone diukur
dengan metode LC / MS / MS yang sensitif dan spesifik
7.2.3 Penyimpanan sampel :
Simpan pada suhu −80 °C (−65 °C to −85 °C) freezer

8. Kriteria Pemasukan Dan Pengeluaran Cuplikan

Data cuplikan dapat dikeluarkan dari studi jika:

a. Subyek muntah setelah minum obat Pioglitazone selama pengambilan sampel

darah
b. Subyek diare selama pengambilan sampel darah

9. Pertimbangan Etik
9.1 Formulir Persetujuan Dari Subyek
 FORMULIR PERNYATAAN PERSETUJUAN UJI KLINIK
(No: 001/04/Form/____/Subjek_Pioglitazone/I/2020)
Yang bertanda tangan di bawah ini:
Nama :

Alamat :
Tempat/Tanggal Lahir :
Pekerjaan :

No. KTP :

Menyatakan bahwa semua penjelasan di atas telah disampaikan kepada saya dan semua
pertanyaan saya telah dijawab oleh dokter, saya mengerti dan bila masih memerlukan
penjelasan, saya akan mendapat penjelasan dari dr.....................................

Demikian pernyataan ini saya buat dengan kesadaran penuh dan tanpa paksaan, dengan
menandatangani surat ini saya setuju untuk menjadi sukarelawan dalam penelitian ini.
Tanggal:

Calon Sukarelawan,

(Nama Jelas)

Diketahui oleh:
Saksi I Saksi II

(Nama Jelas) (Nama Jelas)

 (LEMBAR PENJELASAN PROTOKOL UNTUK SUBYEK)
UJI BIOEKIVALENSI TABLET PIOGLITAZONE

Yth.,

Tim Peneliti laboratorium ...... sedang melakukan penelitian uji bioekivalensi sediaan
tablet Pioglitazone HCl. Penelitian ini bertujuan untuk mengetahui apakah kualitas tablet
Pioglitazone HCl yang diproduksi oleh pabrik Eczacıbas¸ı Pharmaceuticals di Istanbul, Turki
sama baiknya dengan produk inovatornya (Actos®). Hal tersebut dilihat dari
bioavailabilitasnya, yaitu presentase dan kecepatan zat aktif dalam suatu produk obat yang
mencapai sistemik atau tersedianya dalam sirkulasi sistemik dalam bentuk utuh atau aktif
setelah pemberian produk obat, yang dilakukan dengan mengukur kadarnya dalam darah
terhadap waktu. Oleh karena penelitian ini harus dikerjakan pada sukarelawan sehat, maka
kami mengundang Anda untuk ikut serta dalam penelitian ini. Penelitian akan dilakukan dalam
jangka waktu 24 hari.

Bila anda berminat, pertama-tama kesehatan anda akan diperiksa terlebih dahulu.
Untuk itu, kami akan mengambil contoh darah dari pembuluh darah di lengan Anda untuk
memastikan bahwa anda memenuhi syarat. Pemeriksaan meliputi fungsi ginjal dan fungsi hati.
Anda akan diberikan hasil asli pemeriksaan kesehatan ini. Syarat lain yang harus dipenuhi
adalah tidak merokok, sehat, dewasa, berusia 18-55 tahun, tidak hipersensitif dengan
Pioglitazone, tidak punya riwayat gagal jantung, tidak sedang atau pernah mengidap kanker
kandung kemih, dan tidak mengidap hematuria tidak terinvestigasi makroskopik.

Bila Anda memenuhi syarat, pada suatu pagi (tanggal akan ditentukan) Anda akan
diminta datang ke Anapharm Inc, Kanada, setelah sebelumnya puasa semalam setidaknya 10
jam terlebih dahulu. Peneliti akan mengambil darah Anda 15 menit sebelum menelan obat, lalu
setelah minum obat pengambilan darah akan dilakukan pada jam ke 0,5; 1,0; 1,5; 1,75; 2,0;
2,5; 3,0; 3,5; 4.0; 4.5; 5.0; 6.0; 8.0; 10.0; 12.0; 16.0; 24.0; 36.0; 48.0; 72.0; 96.0 dan 120. Setiap
kali pengambilan darah sebanyak 10,0 ml. Anda boleh sarapan dan makan malam pada 4 dan
10 jam setelah obat dikonsumsi. Anda diperbolehkan untuk duduk santai di ruangan yang sudah
disediakan sambil menonton acara televisi atau membaca majalah. Prosedur ini akan diulangi
dua minggu kemudian dengan obat pembandingnya. Obat Pioglitazone ini digunakan sebagai
obat antidiabetik oral.
 Adapun efek samping yang mungkin timbul berupa gejala mati rasa, gangguan
penglihatan, peningkatan berat badan, dan patah tulang.

Penelitian ini akan memberikan manfaat langsung kepada Anda, namun hasilnya akan
dimanfaatkan oleh masyarakat luas.

Anda bebas menolak ikut dalam penelitian ini, dan bila Anda sudah menyatakan
bersedia ikut, juga bebas mengundurkan diri setiap saat selama penelitian berlangsung.
Sebaliknya bila Anda tidak mematuhi instruksi yang diberikan peneliti atau Anda di tengah
penelitian menunjukkan kriteria pengeluaran subyek, Anda juga dapat dikeluarkan dari
penelitian ini setiap waktu.

Keikutsertaan Anda dalam penelitian ini bersifat sukarela dan rahasia. Peneliti akan
merahasiakan semua data identitas Anda. Pada akhir penelitian setiap subjek penelitian akan
diberi insentif sebesar Rp 5.000.000,- sebagai tanda terima kasih berpartisipasi dalam
penelitian.

Penelitian ini telah disetujui oleh Komisi Etik Fakultas Kedokteran ..... Bila Anda
membutuhkan penjelasan lebih lanjut dapat menghubungi penanggung jawab penelitian ...........
dan penanggung jawab medis: dr. ............; Telp: ........

Atas perhatian dan partisipasinya kami mengucapkan terima kasih.

Penanggung Jawab Penelitian

 (LEMBAR EVALUASI EFEK SAMPING OBAT)

DATA SUBYEK
Nama Sukarelawan :
Jenis Kelamin : Laki-laki

Tingkat
Efek yang Mulai Selesai Keterkaitan Keparahan
tidak efek samping
(**)
diinginkan dengan obat
Tanggal Jam Tanggal Jam Ya Tidak

Catatan:
Hubungan sebab akibat dengan uji obat berdasarkan penilaian peneliti:
1 = tidak ada
2 = mungkin
3 = pasif

** Efek samping yang tidak diinginkan dianggap serius jika subyek mengalami:

- Mati rasa
- Gangguan penglihatan
- Patah tulang
- Pasien harus dirawat di rumah sakit.
9.2 Tindakan Darurat
Jika ada reaksi yang tidak diinginkan dari subjek terkait penggunaan obat
Pioglitazone, dapat menghubungi nomor peneliti ………… atau bagian UGD
Rumah Sakit ……. dengan nomor …….. untuk mendapat pertolongan segera.