ABSTRACTBackground: Valsartan is a selective angiotensin II
type 1 receptor blocker indicated for the treatment of hypertension. Although the bioavailability and phar-macokinetic properties of valsartan have been well characterized, a literature search did not identify any reports concerning the bioavailability of valsartan in the Indian population.
Objective: This study was undertaken to compare the pharmacokinetic properties of 2 branded generic valsartan formulations (tests A and B) with a branded innovator product (reference) in healthy Indian male subjects.
Methods: This single-dose, randomized, open-label, 3-period crossover study compared the pharmacokinetic properties of 3 marketed brands of valsartan 160-mg tablets in healthy Indian male volunteers aged 18 to 45 years under fasting conditions. Subjects were as-signed to receive, in randomized order, a single oral dose of 1 of 2 test formulations (A or B) or a reference formulation of valsartan 160 mg. Each study period was separated by a 5-day washout period. Blood sam-ples were collected at prespecified times over a period of 24 hours after administration. An HPLC method was used for the estimation of plasma valsartan con-centrations. A noncompartmental method was em-ployed to determine the pharmacokinetic properties (Cmax, Tmax, AUC0–t, AUC0–∞, and t1/2) to test for bioequivalence. The predetermined regulatory range of 90% CI for bioequivalence was 80% to 125%. Tolera-bility was assessed using physical examination, includ-ing vital sign measurement, and direct questioning.
Results: The study was conducted in 18 subjects (mean age, 24.8 years; weight, 54.5 kg; and height,
164.67 cm). For test formulation A versus the refer-ence formulation, the 90% CIs of the least squares mean test/reference ratios of Cmax, AUC0–t, and AUC0–∞were 81.18% to 115.74%, 77.27% to 108.75%, and 79.32% to 108.70%, respectively. For test B versus reference, the corresponding values were 84.69% to 120.73%, 83.72% to 117.84%, and 84.40% to 115.67%. No adverse events were found or reported by subjects throughout the study.
INTRODUCTIONReducing pharmaceutical care costs with generic drugs while maintaining quality of care is an important soci-etal goal in developed and developing countries.1,2
Health care providers and policy makers also support the practice of prescribing low-cost generic products principally for economic reasons.3 While generic drug
Pharmacokinetics and Bioequivalence Study of Three Oral Formulations of Valsartan 160 mg: A Single-Dose, Randomized, Open-Label, Three-Period Crossover Comparison in Healthy Indian Male Volunteers
Muzaffar Iqbal, PhD1; Arshad Khuroo, PhD2; Lakhvinder S. Batolar, PhD1; Monika Tandon, MD, DM3; Tausif Monif, PhD2; and P.L. Sharma, MD, PhD1
1Department of Pharmaceutical Medicine, Hamdard University (Jamia Hamdard), New Delhi, India; 2Department of Clinical Pharmacology and Pharmacokinetics, Ranbaxy Research Laboratory, Gurgaon, India; and 3Clinical Pharmacology Unit, Fortis Hospital, Noida, India
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innovator (reference) formulation of oral valsartan 160 mg in Indian subjects to obtain bioavailability information in the Indian population and to deter-mine bioequivalence.
SUBJECTS AND METHODSThe clinical study was carried out in accordance with the International Conference on Harmonisation’s Good Clinical Practice Guideline and the principles of the World Medical Association’s Declaration of Helsinki. The study was conducted at Ranbaxy Clinical Phar-macology Unit (RCPU), Jamia Hamdard, New Delhi, India, according to a protocol approved by the Jamia Hamdard institutional review board, Hamdard Na-gar, New Delhi, India.
Subject SelectionThe study group comprised healthy Indian male
volunteers aged 18 to 45 years. Volunteers were se-lected randomly from the volunteer database at RCPU and underwent a standardized screening procedure 14 days before admission into the RCPU. Screening included an evaluation of medical history; demo-graphic data; substance use history; physical examina-tion; 12-lead ECG; chest radiography; and laboratory analysis of hematologic profile, hepatic and renal function, and disease markers for syphilis, HIV, and hepatitis B and C viruses. The volunteers were as-sessed again just before admission. Only medically healthy subjects with clinically normal laboratory profiles were enrolled in the study. Volunteers were instructed not to use any medication other than vita-min preparations before admission and not to con-sume any alcohol-, tobacco-, or xanthine-containing products within 48 hours before admission and dur-ing their stay in the RCPU. Male volunteers of normal weight as per the Life Insurance Corporation of India height/weight chart for nonmedical cases who met the limits of the above evaluation were eligible for partici-pation in the study after voluntarily providing written informed consent.
Exclusion criteria were allergy to any study medi-cation, signs or symptoms of organ dysfunction, sit-ting systolic blood pressure (BP) <100 mm Hg and dia-stolic BP <60 mm Hg, positive urinary drug screen (for cannabinoids and opioids), use of enzyme-modifying drugs within 30 days of admission, or any evaluation parameter significantly outside the reference ranges used at RCPU.
products can reduce the costs of pharmaceutical care by 30% to 80% with respect to their branded counterparts,4 cost savings should not be accepted at the expense of quality of health care.5,6 Interchange-ability between generic and innovator products is of great concern, especially in developing countries, where there may be no provisions for effectively monitoring the quality of marketed generic drug products.7–9
Bioequivalence is defined as the absence of a signifi-cant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.10,11 Bioequivalence studies of generic and innovator products are a routine regulatory practice to obtain approval for the market-ing of generic products.12,13
Valsartan, a nonpeptide orally active angiotensin II receptor blocker with selectivity for the type 1 recep-tor subtype, is indicated for the treatment of hyperten-sion.14 The oral absorption of valsartan is rapid; Tmaxis 2 to 4 hours. The absolute bioavailability of oral valsartan has been reported to be ~25% (range, 10%–35%).15 Valsartan is extensively (85%–99%) bound to plasma proteins, and the mean Vd after admin-istration of an IV bolus of valsartan 20 mg in 12 volun-teers was ~17 L.16,17 Following intravenous adminis-tration, plasma clearance of valsartan was reported to be ~2 L/h, and renal clearance, 0.62 L/h.15
Food was reported to decrease the exposure (as measured by AUC) to valsartan by ~40% and Cmax by ~50%, although from ~8 hours after administration, plasma valsartan concentrations were reported to be similar between the fed and fasted groups.18 This re-duction in AUC was not, however, accompanied by a clinically significant reduction in the therapeutic ef-fect.18 Thus, valsartan is labeled for administration with or without food.18
Although the pharmacokinetic properties of valsar-tan have been reported,17,19–23 a literature search up to January 2010, using the terms valsartan, bioequiva-lence, bioavailability, and India, with no limit of pub-lication years or languages, did not identify any pub-lications concerning the bioavailability of valsartan in the Indian population.
The present study was undertaken to determine and compare the pharmacokinetic properties of 2 branded generic (test) formulations with those of a branded
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Sample Collection and ProcessingA total of 54 blood samples of 4 mL each were
collected from each volunteer into tubes containing EDTA (Vacutainer, Becton, Dickinson and Company, Franklin Lakes, New Jersey) through an indwelling ve-nous catheter placed in a forearm vein. Samples were collected for pharmacokinetic assessment before (base-line) and at 0.5, 1, 1.5, 2, 2.33, 2.67, 3, 3.33, 3.67, 4, 4.5, 5, 6, 8, 12, 18, and 24 hours after administration in each period. The baseline blood sample in each pe-riod was collected in a single aliquot, within a period of ~1.5 hours before administration; postdose samples were collected within 2 minutes of the scheduled times.
After collection, blood samples were centrifuged at 4000 rpm for 15 minutes at 4°C to separate plasma. All plasma samples were divided into 2 aliquots and transferred to suitable labeled tubes and rechecked to ensure transfer of plasma to the correct tube. The plasma samples were stored at ≤–15°C until they were packed with dry ice and transferred to the analytical facility (Department of Clinical Pharmacology and Pharmacokinetics, Ranbaxy Research Laboratory, Gurgaon, India) for assay.
HPLC Method Development and ValidationThe HPLC method used for the estimation of val-
sartan in human plasma was developed and validated at the Department of Clinical Pharmacology and Pharmacokinetics. Irbesartan was used as the internal standard (IS). The HPLC instrumentation setup from Shimadzu Corporation, Tokyo, Japan, consisted of an SCL-10A system controller, LC-10 AT/AD pump, SIL-10 A autoinjector with a cooling rack, SPD-10A/10AV UV-Visible Detector, CTO-10A column oven, and Class LC 10/VP software for data processing. All solvents were HPLC grade, whereas other chemicals and reagents were analytical grade. Valsartan working standard (purity, 98.3%, SynFine Research, Rich-mond Hill, Ontario, Canada) and irbesartan working standard (purity, 99.8% of US Pharmacopeia refer-ence standard) were provided by Ranbaxy Research Laboratory. The mobile phase consisted of 20-mM potassium dihydrogen orthophosphate buffer (pH adjusted to 2.7 ± 0.05 using 50% orthophosphoric acid):acetonitrile (60:40 vol/vol), eluted at a flow rate of 1.2 mL/min having RP Select B (Lichrosphere, Agilent Technologies, Inc., Santa Clara, California) (column, 250 × 4.0 mm; particle size, 5 µm). The effluent was monitored using ultraviolet detection set at 225 nm,
Study Design and Products EvaluatedThis single-dose, randomized, open-label, balanced,
3-period crossover study compared 2 branded gener-ic formulations (A* [lot no. C6027003; expiration, April 2009] and B† [lot no. A7002MP; expiration, April 2009]) and a branded innovator formulation‡
(lot no. S0056; expiration, March 2009) of valsartan 160-mg tablets in healthy Indian male subjects. The representative test products were chosen based on the costs of retail pricing. The 2 lower-cost test products were compared with the most expensive innovator product.
Study Drug AdministrationSubjects were assigned to receive, in randomized
order per a computer-generated balanced randomiza-tion schedule (SAS Institute Inc., Cary, North Caroli-na), a single oral dose of 1 of the 2 test formulations or the reference formulation of valsartan 160 mg. Study periods were separated by a 5-day washout period. Study drugs were administered after an over-night fast of ≥10 hours, with 240 mL of water, under the supervision of a trained health care professional (MBBS or MD degree).
Admission and StaySubjects were admitted to the RCPU 24 hours be-
fore the administration of the first dose of study drug (period 1). During periods 2 and 3, all of the subjects reported to the RCPU ≥12 hours before administra-tion on day 1. After blood sampling for 24 hours after administration on day 1, subjects were discharged on the morning of day 2. Subjects were asked to refrain from food intake for 4 hours after administration. Water was disallowed from 1 hour before dosing until 2 hours after administration. Subjects received stan-dardized meals at 4, 9, and 13 hours after adminis-tration (lunch, snacks, and dinner, respectively) in all 3 study periods.
Compliance was assessed using a thorough exami-nation of the oral cavity by trained study personnel after administration and using measurements of plasma valsartan concentrations during the analytic phase.
The HPLC procedure described was applied to the subjects’ samples and to the extraction of samples for calibration curve and QC process. One subject’s ana-lytical batch consisted of a total of 77 samples, includ-ing all of the samples from 1 subject (57) in 3 periods, together with the calibration standards (14) and QC samples (2 low QC, 2 medium QC, and 2 high QC).
ature, BP, and radial pulse—were measured during ad-mission and before and at 3, 8, 12, and 24 hours after study drug administration in each period. Brief clinical examinations were conducted by a qualified medical designate (MBBS or MD degree) before study drug ad-ministration and at discharge. Subjects were also specifi-cally asked about any adverse events every 4 hours for 12 hours after administration and at discharge.
Pharmacokinetic and Statistical AnalysesA noncompartmental pharmacokinetic method
was employed to determine the pharmacokinetic pa-rameters of valsartan using WinNonlin-Node 4.0 (Pharsight Corporation, Mountain View, California). AUC0–t was calculated using the linear trapezoidal method. AUC0–∞ was calculated as the sum of AUC0–tand the ratio of the last measured plasma concentra-tion over the time span specified. Cmax was calculated as the maximum measured plasma concentration over the time span specified. The ke value was calculated from a semilog plot of the plasma concentration–time curve.
Statistical analyses were conducted using SAS ver-sion 9.1 (SAS Institute Inc.). The analysis included data from all subjects who completed the study. The log-transformed pharmacokinetic parameters (Cmax, AUC0–t, and AUC0–∞) were analyzed using a mixed-effects ANOVA model using Type III sum of squares, with the main effects of sequence, period, and formu-lations as fixed effects and subjects nested within se-quence as random effect. The sequence effect was tested at the 0.10 level of significance, and other main effects were tested at the 0.05 level of significance against the residual error (mean square error) from the ANOVA model as the error term. Each ANOVA included a calculation of least squares means (LSMs), the difference between the adjusted formulation means, and the SE associated with the difference. The parameter Tmax was statistically evaluated using the
with column oven temperature 40°C and sample cooler temperature 8°C ± 0.2°C. No significant inter-ference at the retention times of valsartan (10–12 min-utes) and IS (7–9 minutes) was observed on chroma-tography of blank plasma under the aforementioned conditions. The peak area was measured for calcula-tion of the peak area ratio of valsartan to IS, and the concentrations were estimated.
The method was developed and validated in terms of selectivity, linearity, precision, accuracy, sensitivity, recovery, and stability (stock solution, benchtop, freeze–thaw, autoinjector, and long-term and dilution integrity) according to the US Food and Drug Ad-ministration (FDA) guideline for bioanalytical method validation.24 To assess linearity, the plasma calibra-tion curve (range, 217.7–6118.4 ng/mL) was pre-pared and assayed in triplicate on 3 separate days. Quality control (QC) samples (lower limit of quanti-tation, 218.2 ng/mL; low QC, 431.3 ng/mL; medi-um QC, 2269.7 ng/mL; and high QC, 4539.5 ng/mL) were analyzed to assess the accuracy and precision of the method. Interbatch precision (%CV) was <7.4%, and accuracy (% theoretical) ranged between 103.4% to 109.5%. Intrabatch precision (%CV) was <8.9% and accuracy (% theoretical) ranged between 99.2% and 112.5%. All of the other parameters, such as se-lectivity, linearity, ruggedness, recovery, and stability, were within the normal range according to the FDA guideline.24
Sample Preparation and AnalysisAn aliquot of human plasma containing both ana-
lyte and IS was extracted using a liquid–liquid extrac-tion method. The blank human plasma, calibration standards, QC, and unknown samples were thawed for 30 minutes and vortexed for 30 seconds. Fifty microliters (40 µg/mL) of irbesartan (except blank sample) and 50 µL of 50% formic acid were added to 500 µL of plasma sample. The samples were vortex-mixed for ~1 minute and 5 mL of ethyl acetate + N-hexane (80:20 vol/vol) was added. The samples were mechanically shaken for 20 minutes at 100 rpm and centrifuged for 5 minutes at 4000 rpm at 4°C. After centrifugation, 3.5 mL of supernatant was trans-ferred to a clean tube and evaporated to dryness under a stream of nitrogen at 50°C in a nitrogen evaporator dryer. The residue was reconstituted in 500 µL of mo-bile phase, and 40 µL was transferred into an HPLC vial for analysis.
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158–177 cm]). All of the subjects completed the study, with the exception of 1 subject who withdrew for per-sonal reasons.
PharmacokineticsThe mean plasma concentration–time curves after
single-dose oral administration of all 3 of the valsar-tan 160-mg oral formulations are shown in the figure. Comparisons of the pharmacokinetic parameters be-tween the 3 formulations are shown in Table I.
The mean (SD) pharmacokinetic properties of test formulation A were as follows: Cmax, 6.11 (2.98) μg/mL; Tmax, 2.71 (0.86) hours; AUC0–t, 33.18 (17.50) μg/mL/h; and AUC0–∞, 35.32 (17.54) μg/mL/h.
The mean (SD) pharmacokinetic properties of the test formulation B were as follows: Cmax, 5.94 (2.04) μg/mL; Tmax, 2.24 (1.07) hours; AUC0–t, 33.87 (13.77) μg/mL/h; and AUC0–∞, 35.89 (14.09) μg/mL/h.
With the reference formulation, the pharmacokinetics were: Cmax, 5.94 (2.37) μg/mL; Tmax, 2.90 (1.07) hours;
Wilcoxon signed rank test at the α = 0.05 level of significance.
CIs consisted of two 1-sided t tests for bioequiva-lence; 90% CIs for the difference between treatment in LSMs were calculated for the parameters (Cmax, AUC0–t, and AUC0–∞) using log-transformed data. The CIs were expressed as a percentage relative to the LSM of the reference formulation. Test/reference ratios of the LSMs were calculated using log-transformed Cmax, AUC0–t, and AUC0–∞. Ratios of means were expressed as a percentage of the LSM for the reference formula-tion. Intrasubject variability (%CV) and power were also calculated. The predetermined regulatory range of 90% CI for bioequivalence was 80% to 125%.
RESULTSDemographic Data
Eighteen subjects were enrolled in the study (mean age, 24.8 years [range, 20–34 years]; weight, 54.5 kg [range, 46–69 kg]; and height, 164.67 cm [range,
0.5
0
Plas
ma
Vals
arta
n C
once
ntra
tion
(µg/
mL)
20151050
Time After Study Drug Administration (h)
25
1.0
1.5
3.0
4.5
5.0
3.5
4.0
2.0
2.5
Test ATest BReference
Figure. Linear plot of mean plasma valsartan concentrations versus time of 2 test formulations (A, Valzaar®
[Torrent Pharmaceuticals Ltd., Gujarat, India]; B, Valent® [Lupin Ltd., Mumbai, India]) and a refer-ence formulation (Diovan®, Novartis India Ltd., Mumbai, India) of single-dose oral valsartan 160 mg in healthy Indian male volunteers (n = 17).
March 2010 593
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data of Cmax, AUC0–t, and AUC0–∞ were 31.2, 30.0, and 27.6, respectively (Table III).
No significant differences in Tmax were found be-tween the test and reference products.
TolerabilityNo adverse events were found or reported by any
of the subjects throughout the study.
DISCUSSIONThe findings from this study suggest that test formula-tion B and the reference formulation were bioequiva-lent but that test formulation A and the reference formulation were not, based on the 90% CIs of the log-transformed data.11,12 Test formulation A was not considered bioequivalent because the 90% CI of the LSM ratios did not fall within the regulatory range of 80% to 125%. This finding may have been due to an inadequate sample size—the powers calculated for AUC0–t and AUC0–∞ were 56.25% and 63.53%, re-
AUC0–t, 34.52 (15.74) μg/mL/h; and AUC0–∞, 36.60 (15.68) μg/mL/h.
The mean (SD) t1/2 values for the test and reference formulations were 4.23 (1.55), 4.25 (1.21), and 4.31 (0.99) hours, respectively. The plasma ke values for these products were calculated as 0.181 (0.05), 0.175 (0.04), and 0.169 (0.03) h–1, and the AUC0–t/AUC0–∞ ratios were 92.95 (5.03), 93.78 (2.37), and 93.42 (3.69).
BioequivalenceThe 90% CIs for the test A/reference LSM ratios
of the log-transformed data for Cmax, AUC0–t, and AUC0–∞ were 81.18% to 115.74%, 77.27% to 108.75%, and 79.32% to 108.70%, respectively. For the test B/reference ratios, the corresponding values were 84.69% to 120.73%, 83.72% to 117.84%, and 84.40% to 115.67% (Table II).
No treatment, period, or sequence effects were found on ANOVA of Cmax, AUC0–t, and AUC0–∞. The intrasubject variabilities (%CVs) for the log-transformed
Table I. Pharmacokinetic (PK) properties of 2 test formulations and 1 reference formulation of single-dose oral valsartan 160 mg in healthy Indian male volunteers (n = 17).
ence) after single-dose administration in 40 healthy volunteers. Both formulations were considered bioequivalent because the 90% CIs of the mean treat-ment ratios of log-transformed Cmax and AUC values were within the range of 0.80 to 1.25.21 In the second study, valsartan 320-mg capsules (test) and valsartan 320-mg tablets (reference) were assumed to be bio-equivalent based on the 95% CIs of the mean treat-ment ratios of log-transformed Cmax, Tmax, and AUC values in 15 male healthy volunteers.22 In the third study, a test and a reference formulation of valsartan 160-mg tablets were found to be bioequivalent.23 The present study compared the bioavailability of 3 formu-
spectively, and intrasubject %CVs were 30.0% and 27.6%. In retrospect, the sample sizes required to generate >80% power were calculated as 60 and 42 for AUC0–t and AUC0–∞, respectively. Thus, it was concluded that the study had not been designed with an adequate sample size to overcome the intrasubject variability, and adequately designed studies to assess test formulation A are needed. High intrasubject vari-ability support previously reported high variability of valsartan.21,23 Three bioequivalence studies (2, cap-sules vs tablets; 1, tablets vs tablets) of valsartan are reported in the literature. In one study, 320-mg tablets (test) were compared with 2 × 160-mg capsules (refer-
Table III. Mixed-effects ANOVA of the pharmacokinetic (PK) properties of 2 test formulations*† and 1 refer-ence formulation‡ of single-dose oral valsartan 160 mg in healthy Indian male volunteers (n = 17).
Effect
Intrasubject PK Parameter Treatment Period Sequence Power, % %CV
Table II. Summary statistics of the pharmacokinetic (PK) properties of 2 test formulations and 1 reference formulation of single-dose oral valsartan 160 mg in healthy Indian male volunteers (n = 17).
LSM Treatment Ratio (90% CI)
PK Parameter* Test A† vs Reference‡ Test B§ vs Reference
LSM = least squares mean. * Values are log-transformed. † Trademark: Valzaar® (Torrent Pharmaceuticals Ltd., Gujarat, India). ‡ Trademark: Diovan® (Novartis India Ltd., Mumbai, India). § Trademark: Valent® (Lupin Ltd., Mumbai, India).∥Value lies outside the predetermined range for bioequivalence (80%–125%).
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4. Snow Jr DB. Maximising generic utilisation: The power of pharmacy benefit management. J Gen Med. 2007;5:27–38.
5. Meredith PA. Generic drugs. Therapeutic equivalence. Drug Saf. 1996;15:223–242.
6. Spino M, Tsang Y, Pop R. Dissolution and in vivo evidence of differences in reference products: Impact on develop-ment of generic drugs. Eur J Drug Metab Pharmacokinet. 2000;25:18–24.
7. Pincock S. WHO tries to tackle problem of counterfeit medicines in Asia. BMJ. 2003;327:1126.
8. Khan AY, Ghilzai NM. Counterfeit and substandard qual-ity of drugs: The need for an effective and stringent regula-tory control in India and other developing countries. Ind J Pharmacol. 2007;39:206–207.
9. Dos Reis Serra CH, Mori Koono EE, Kano EK, et al. Bioequivalence and pharmacokinetics of two zidovudine formulations in healthy Brazilian volunteers: An open- label, randomized, single-dose, two-way crossover study. Clin Ther. 2008;30:902–908.
10. US Dept of Health and Human Services (HHS), Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER). Guidance for Industry. Bioavail-ability and bioequivalence studies for orally administered drug products—general considerations. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/How DrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM154838.pdf. Accessed November 13, 2008.
11. Central Drugs Standard Control Organization, Director-ate General of Health Services, Ministry of Health & Family Welfare. Guidelines for bioavailability & bioequivalence studies. http://www.cdsco.nic.in/htmL/BE%20Guidelines %20Draft%20Ver10%20March%2016,%2005.pdf. Accessed November 13, 2008.
12. Al-Jazairi AS, Bhareth S, Eqtefan IS, Al-Suwayeh SA. Brand and generic medications: Are they interchangeable? Ann Saudi Med. 2008;28:33–41.
13. Nakai K, Fujita M, Ogata H. International harmonisation of bioequivalence studies and issues shared in common. Yakugaku Zasshi. 2000;120:1193–1200.
14. Markham A, Goa KL. Valsartan. A review of its pharma-cology and therapeutic use in essential hypertension. Drugs. 1997;54:299–311.
16. Colussi DM, Parisot C, Rossolino ML, et al. Protein bind-ing in plasma of valsartan, a new angiotensin II receptor antagonist. J Clin Pharmacol. 1997;37:214–221.
17. Flesch G, Müller P, Lloyd P. Absolute bioavailability and pharmacokinetics of valsartan, an angiotensin II receptor antagonist, in man. Eur J Clin Pharmacol. 1997;52:115–120.
18. UK Summary of Product Characteristics: Diovan. http://emc.medicines.org.uk/document.aspx?documentId=1279. Accessed May 13, 2009.
lations (2 test and 1 reference) of valsartan 160-mg tablets in Indian volunteers.
Valsartan is rapidly absorbed, based on the mean (SD) Tmax values in the present study—2.71 (0.86), 2.24 (1.07), and 2.90 (1.07) hours after the adminis-tration of test formulation A, test formulation B, and the reference formulation, respectively. AUC0–t/AUC0–∞values for all 3 products were >80%, suggesting that the duration of sample collection was appropriate, covering >80% of the complete drug profile. Overall, valsartan was well tolerated in all of the subjects, with no adverse events reported during the study.
Study LimitationsDue to a constraint of the research funds, 18 volun-
teers were enrolled in this study, and due to the high intrasubject %CVs, a larger sample size is needed to confirm the results. Because the study was performed only in healthy male volunteers, the findings cannot be generalized to other populations.
CONCLUSIONSThis small, single-dose study found that test formula-tion B and the reference formulation of valsartan 160 mg met the regulatory criteria for bioequivalence, but that formulation A and the reference product did not. All 3 formulations were well tolerated.
ACKNOWLEDGMENTSThis research was financially supported by Ranbaxy Laboratories Ltd., Gurgaon, India, as a part of the Doctoral degree in Pharmaceutical Medicine awarded by Hamdard University (Jamia Hamdard), New Delhi, India. The sponsor had no role in the design, conduct, selection of brand, or publication of the results. The authors have indicated that they have no other con-flicts of interest regarding the content of this article.
The authors thank Ranbaxy Research Laboratory for providing clinical and analytical facilities to con-duct this study.
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2. Pitt B. Generic drugs in cardiology: Will they reduce health care costs? J Am Coll Cardiol. 2004;44:10–13.
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19. Müller P, Flesch G, de Gasparo M, et al. Pharmacokinetics and phar-macodynamic effects of the angio-tensin II antagonist valsartan at steady state in healthy, normoten-sive subjects. Eur J Clin Pharmacol. 1997;52:441–449.
20. Sioufi A, Marfil F, Jaouen A, et al. The effect of age on the pharma-cokinetics of valsartan. Biopharm Drug Dispos. 1998;19:237–244.
21. Séchaud R, Graf P, Bigler H, et al. Bioequivalence study of a valsartan tablet and a capsule formulation after single dosing in healthy vol- unteers using a replicated crossover design. Int J Clin Pharmacol Ther. 2002;40:35–40.
22. Pérez M, Cardenas W, Quim GR, et al. A comparative, cross-over, double blind, randomized study for bioequivalence assessment between two formulations of valsartan cap-sules vs tablets. Revista Colombia Médica. 2006;37:114–120.
23. Franco Spínola AC, Almeida S, Filipe A, et al. Results of a single-center, single-dose, randomized-sequence, open-label, two-way crossover bio- equivalence study of two formula-tions of valsartan 160-mg tablets in healthy volunteers under fasting conditions. Clin Ther. 2009;31:1992– 2001.
24. US Dept of Health and Human Ser-vices (HHS), Food and Drug Ad-ministration (FDA), Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CVM). Guidance for Industry. Bio-analytical method validation. http:// www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/UCM070107. pdf. Accessed November 13, 2008.
Address correspondence to: Muzaffar Iqbal, PhD, Faculty of Pharmacy, King Saud University, PO Box 2457, Riyadh, KSA. E-mail: [email protected]
