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Asian journal of drug metabolism and pharmacokinetics

Asian Journal of Drug Metabolism and Pharmacokinetics
Copyright by Hong Kong Medical Publisher
ISSN 1608 2281 2004; 4(2): 119-122
Study on bioequivalence of pioglitazone hydrochloride tablets
in healthy Chinese volunteers

Hua Zhang, Xue-Qing Wang, Xuan Zhang, Qiang Zhang, Qi Yin* and Ke-Xin Li*
Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100083, China
*Clinical Drug Reserch Base, Beijing Hospital, Beijing 100730, China
Abstract
Aim This study was to investigate the pharmacokinetics of pioglitazone after a single oral dose of
pioglitazone hydrochloride tablets in healthy Chinese volunteers and to evaluate the bioequivalence
between the test and the reference tablets. Methods Twenty healthy Chinese volunteers received a
single oral dose of 30mg pioglitazone either as test or as reference tablet in a randomized, open label,
two-way crossover study. Pioglitazone in human plasma was determined by a HPLC method. Results
Mean maximum concentration (Cmax) of pioglitazone was 1.85 mg
L-1 at 1.9 hours for reference tablets. Mean area under the plasma concentration-time curve from zero to last measured point (AUC0-t) for test was 15.51mg h L-1 compared with 15.37 mg h L-1
for reference. The analysis of variance on Cmax and AUC indicated that there was no significant
difference between the two formulations. All 90% confidence intervals (CIs) of the test/reference
geometric mean ratio were within the bioequivalence limits. Conclusion The test tablets were
bioequivalent with the reference tablets.
Key words
pioglitazone hydrochloride; tablets; bioequivalence; pharmacokinetics; high performance liquid chromatography Introduction
Material and Methods
Test and reference drugs
(5-ethyl-2-pyridinyl)ethoxy]phenyl] methyl}-2,4- The standard substance and the test tablet of thiazolidinedione hydrochloride salt, is an oral pioglitazone hydrochloride were obtained from Libao anti-hyperglycemic agent which acts primarily by Pharmaceutical Co. Ltd (Shenzhen, China), and each decreasing insulin resistance and was developed by test tablet contents 15mg of pioglitazone Takeda chemicals. Piogliazone hydrochloride was hydrochloride. The reference tablets, Actlns®, were marked several years ago and used in the treatment of produced by Taiyang Pharmaceutical Co. Ltd diabetes(non-insulin-dependent diabetes (Beijing, China), and each reference tablet contents mellitus, NIDDM)[1] . This study was to investigate the pharmacokinetics of pioglitazone after a single oral dose of pioglitazone hydrochloride tablets in Subjects
healthy Chinese volunteers and to evaluate the Twenty healthy Chinese male subjects ranging bioequivalence between the test and the reference Correspondence to Dr. Zhang Xuan. Department of Pharmaceutics, Before enrollment, each subject was determined to be School of Pharmaceutical Sciences, Peking University, Beijing in good health through medical history, physical 100083, China. Phn +86-10-82802684. Fax +86-10-82802791; examination, electrocardiograms (ECGs) and routine laboratory tests. No medications were used for at and 0.1 mol·L-1 ammonium acetate (pH 4.5) as least two weeks before the study. Tobacco and 39:61(v/v). A constant flow rate of 1 ml·min-1 was alcohol were forbidden throughout the studying periods. One week after finishing the study, the was monitored at a wavelength of 269 nm and The study protocol followed the guideline of the Hesinki Declaration and was approved by the Standard curve
local independent ethic committee. Written informed According to above method the linearity was consent was obtained from each subject before the evaluated by constructing a calibration curve with pioglitazone deferent concentration. The deferent concentrations of pioglitazone were prepared for 0, Study design
0.025, 0.050, 0.100, 0.250, 0.500, 1.000, and 2.000 A single-dose, randomized, open label, two-way µg·mL-1. The linearity was tested by linear regression crossover study was carried out in 20 healthy Chinese between peak area and the concentration of the male subjects. The participants were randomly divided into two groups. Each volunteer fasted for about 12 h was random assigned to receive two test Recovery and precision
or reference tablets containing 30 mg pioglitazone The recovery and precision were calculated hydrochloride with 200 mL water at 7:00 AM and according to the routine method at low, middle and continued fasting for 4 h. The wash-out period was high concentration of 0.050, 0.100 and 0.250 µg·mL-1 Sample collection
Pharmacokinetics
Venous blood samples (5mL) were collected in The plasma drug concentration data were treated heparinized tubes prior to drug administration (0 h) by the Practical Pharmacokinetic Program (3P97) and at 0.33, 0.66, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 9.0, edited by the Chinese Mathematical Pharmacological 12.0, 24.0, and 36.0 h after dosing. After the Society. The concentration-time curves were fitted centrifugation at 3000 r min-1 for 10 min, the plasma automatically by this program. The Cmax and Tmax were isolated and stored in tubes at –20 were obtained directly from the observed concentration data. AUC were calculated by the trapezoidal method. The relative bioavailability (F) Sample preparation
was calculated by the following equation: F=(AUCtest/AUCreference)
K2HPO4 was vortex-mixed in a 10 mL glass tube for 30 second, then 5 ml ethyl acetate were added into Statistical analysis
the tube, and it was vortex-mixed again for 3 min. After the centrifugation at 3500 r min-1 for 6 min, the evaluated by t test for statistical analysis. The level of 4 mL of organic phase was removed into another tube and was evaporated to dryness under a nitrogen was assessed using an analysis of variance and two one-sided t-test. AUC, Cmax, and t1/2 were logarithmic of sample solution was injected onto the HPLC Analytical procedure
According to the protocol approved by Ethics Chromatography
Committee, the safety examination of volunteers was Agilent high performance liquid recorded on Case Record Form by doctors. chromatography (HPLC) system (1100 series) was used for the determination of pioglitazone in plasma samples. The mobile phase consisted of acetonitrile concentration-time curves of pioglitazone are shown Method validation
in Fig 1. The pharmacokinetic parameters of the two The linear equation was Y=0.1028X+1.5022(Y: pioglitazone hydrochloride formulations are listed in area and X: concentration, r=0.9998, n=5) at range of 0.025 to 2.000µg·mL-1. The extracted recovery was more than 70%, and RSD for intra- and inter-day Bioequivalence evaluation
assay was less than 10%. The limit of quantitation The analysis of variance on Tmax, Cmax and AUC indicated that there was no significant difference between the two products. The parameter AUC (90% CIs of the test/reference geometric mean ratio 91.3-108.6%) and Cmax (90% CIs of the test/reference geometric mean ratio 88.5-108.9%) were well within the acceptance criteria for bioequivalence. According to the CRF, no side effects of any kind or disorders, which could be attributed to the drug, were observed. All volunteers completed the study without referring any abnormality. No objective
Discussion
determining pioglitazone in biological fluids[2-5]. Comparing to the published methods, the approach we established was also a rapid, sensitive and Fig 1 The mean plasma concentration-time curves of selective method for the determination of pioglitazone after a single oral administration of test or reference tablet containing 30mg pioglitazone According to the papers in literature[2], we found hydrochloride in 20 Chinese healthy subjects (mean that the Cmax of pioglitazone in Chinese volunteers was high comparing with that in west volunteers. Table 1 Pharmacokinetic parameters of pioglitazone after After oral dose with 15mg of pioglitazone a single oral administration of test or reference tablet hydrochloride tablet, the Cmax was 0.524 µg·mL-1 in containing 30mg pioglitazone hydrochloride in 20 Chinese west volunteers, and with 30mg of pioglitazone The relative bioavailability of the test tablet over the reference tablet was 101.9%. Statistic analysis (two-way one t-test in Cmax, AUC0-t and AUC0- ) exhibited that the test tablets were bioequivalence References
1 Chilcott J, Tappenden P, Jones ML, Wight JP. A Systematic Pharmacokinetics
review of the clinical effectiveness of pioglitazone in the After a single oral administration of pioglitazone treatment of type-2 diabetes mellitus. Clin Therap 2001; hydrochloride tablets of test and reference containing 30mg pioglitazone hydrochloride in 20 healthy 2 Xuea YJ, Kenneth C, Turner JB, Meeker JP, Mark A, Steve U. Quantitative determination of pioflitazone in human serum by direct-injection high-performance liquid chromatography mass spectrometry and its application to a bioequivalence pioglitazone and its metabolites in human serum by liquid study. J Chromatogr B, 2003; 795 : 215–226 chromatography and solid phase extraction. J Pharm 3 Zhong WZ, Lakings DB. Determination of pioglitazone in dog serum using solid phase extraction and high performance Yamashita K, Murakami H, Okuda T, Motohashi M. liquid chromatography with ultraviolet (229 nm) detection. J High-performance liquid chromatographic determination of pioglitazone and its metabolites in human serum and urine. J Zhong Wz and Williams MG. Simultaneous quantitation of

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Curriculum vitae

CURRICULUM VITAE Birth Date: Citizenship: Current Position: Chief Professor, Department of Anatomy (Division of Cell biology), School of Medicine, Iwate Medical University (Morioka, Japan) Education: Doctor of Medicine, Asahikawa Medical College Bachelor of Medicine, Iwate Medical University Employment: Chief Professor, Department of Anatomy (Division of Cell biology),

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