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Purpose: Our study evaluated adverse events of therapeutic failure (and specifically reduced duration of action) with the use of a branded product, Osmotic Release Oral System (OROS) methylphenidate, which is approved for the treatment of attention deficit/hyperactivity disorder, and a generic product (methylphenidate, methylphenidate ER-C), which was approved for marketing in Canada based on bioequivalence to OROS methylphenidate. This study was initiated following reports that some US-marketed generic methylphenidate ER products had substantially higher reporting rates of therapeutic failure than did the referenced brands., Methods: Through methodology similar to that used by the US Food and Drug Administration to investigate the issue with the US-marketed generic, reporting rates were calculated from cases of therapeutic failure identified in the Canadian Vigilance Adverse Reaction Online database for a 1-year period beginning 8 months after each product launch. Corresponding population exposure was estimated from the number of tablets dispensed. An in-depth analysis of narratives of individual case safety reports (ICSRs) with the use of the generic product was conducted in duplicate by 2 physicians to assess causality and to characterize the potential safety risk and clinical pattern of therapeutic failure. Similar secondary analyses were conducted on the US-marketed products., Findings: Reporting rates of therapeutic failure with the use of methylphenidate ER-C (generic) and OROS methylphenidate (brand name) were 411.5 and 37.5 cases per 100,000 patient-years, respectively (reporting rate ratio, 10.99; 95% CI, 5.93-22.21). In-depth analysis of narratives of 230 ICSRs of therapeutic failure with the Canadian-marketed generic determined that all ICSRs were either probably (60 [26%]) or possibly (170 [74%]) causally related to methylphenidate ER-C. Clinical symptoms suggestive of overdose were present in 31 reports of loss of efficacy (13.5%) and occurred primarily in the morning, and premature loss of efficacy (shorter duration of action) was described in 98 cases (42.6%) and occurred primarily in the afternoon. Impacts on social functioning, such as disruption in work or school performance or adverse social behaviors, were found in 51 cases (22.2%)., Implications: The ~10-fold higher reporting rate of therapeutic failure with the generic product relative to its reference product in the present Canadian study resembles findings with US-marketed generic products. While these results should be interpreted with caution due to the limitations of spontaneous adverse event reporting, which may confound comparisons across products, similar findings nonetheless led the US Food and Drug Administration to declare in 2014 that 2 methylphenidate ER generic products in the United States were neither bioequivalent nor interchangeable with OROS methylphenidate-their reference product. Our results indicate a potential safety issue with the Canadian-marketed generic and suggest a need for further investigation by Health Canada., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Generic formulations are by far the most prescribed drugs. This scenario is highly beneficial for society because medication expenses are significantly reduced after expiration of the exclusivity period conceded to the branded name drug. Correspondingly, these formulations must be adequately evaluated to avoid drug inefficacy and toxicity in the overall patient population. Bioequivalence studies are the only in vivo evaluation that a generic drug must overcome to reach the market. These clinical trials have not been exempt from underrepresentation of female subjects and a lack of sex-based analysis. Frequently, conclusions obtained in men are extrapolated to women. Furthermore, the obtained results are not analyzed to determine sex differences. The aim of this study was to discuss the effect that male and female differences in gastrointestinal physiology can have on bioequivalence conclusions and to show why a sex-based analysis must be conducted in these studies to improve the evaluation of generic drugs., Methods: This discussion was based on observed sex differences in product bioavailability discrimination (sex-by-formulation interaction) and on residual variability through an analysis of average bioequivalence data previously reported by other researchers and data collected by our center. Bioequivalence studies of oral formulations, with a 2-period, 2-sequence, 2-treatment random crossover design performed in healthy subjects with at least 6 subjects of each sex, were included. In addition, the bioequivalence conclusion that would have been reached in each study if performed with only 1 sex was estimated., Findings: The data reveal that differences in both product bioavailability discrimination and residual variability occur with a significant incidence in bioequivalence studies. In either C max or AUC, a significant sex-by-formulation interaction was present in 1 of 3 reviewed studies, whereas differences in residual variability between sexes were significant for >50% of studies. Moreover, the performed estimations suggest that the reported bioequivalence conclusions were not verified in at least 1 sex for 1 of 3 studies and were not verified in men and in women for 1 of 6 studies., Implications: This research shows that extrapolation of bioequivalence results from the male population to the female population is not always valid. Bioequivalence studies must therefore be performed with both male and female subjects in similar proportions. Sex-based analysis in bioequivalence can improve study design, enhance the representativeness of conclusions, and provide important information regarding formulation performance, thereby promoting the efficacy and safety of generic drugs., (Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.)

Purpose: NSAIDs are commonly prescribed for the treatment of pain and inflammation. Despite the effectiveness of NSAIDs, concerns exist regarding their tolerability. Worldwide health authorities, including the European Medicines Agency, Health Canada, and the US Food and Drug Administration, have advised that NSAIDs be prescribed at the lowest effective dosage and for the shortest duration. Effective lowering of NSAID dosage without compromising pain relief has been demonstrated in randomized, controlled trials of the recently approved NSAID lower-dose submicron diclofenac. Building on previously published work from an independently published systematic review and meta-analysis, a linear dose-toxicity relationship between diclofenac dose and serious gastrointestinal (GI) events was recently demonstrated, indicating that reductions in adverse events (AEs) may be seen even with modest dose reductions in many patients. The objective of the present study was to estimate the potential reduction in risk for NSAID dose-related AEs, corresponding savings in health care costs, and the incremental cost-effectiveness of submicron diclofenac compared with generic diclofenac in the United States., Methods: Our decision-analytic cost-effectiveness model considered a subset of potential AEs that may be avoided by lowering NSAID dosage. To estimate the expected reductions in upper GI bleeding/perforation and major cardiovascular events with submicron diclofenac, our model used prediction equations estimated by meta-regressions using data from systematic literature reviews. Utilities, lifetime costs, and health outcomes associated with AEs were estimated using data from the literature. The face validity of the model structure and inputs was confirmed by clinical experts in the United States. Results were evaluated in 1-way and probabilistic sensitivity analyses., Findings: The model predicted that submicron diclofenac versus generic diclofenac could reduce the occurrence of modeled GI events (by 18.0%), cardiovascular events (by 6.9%), and acute renal failure (by 18.8%), leading to a 9.8% reduction in costs of treating AEs. Submicron diclofenac was predicted to be cost-saving, with results relatively insensitive to parameter uncertainty., Implications: Submicron diclofenac has the potential to provide clinical and economic value to patients using NSAIDs in the United States. Further investigation regarding the potential effects of submicron diclofenac on the risks for additional NSAID dose-related toxicities should be explored., (Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.)

Purpose: High cholesterol, especially high low-density lipoprotein cholesterol (LDL-C), is an important risk factor for cardiovascular disease (CVD) morbidity/mortality. Switching from high-efficacy lipid-lowering therapies (HETs) to simvastatin might lead to sub-optimal control of LDL-C. Our objective was to evaluate the impact of switching from HETs to generic simvastatin on LDL-C levels and LDL-C goal attainment among the high-risk primary and secondary prevention populations in the United Kingdom., Methods: This retrospective cohort study was conducted using Clinical Practice Research Datalink database. Included were individuals with more than 2 months of prescriptions of the following HETs between August 1, 2004 and December 31, 2008: simvastatin/ezetimibe fixed dose (S/E), simvastatin and ezetimibe co-administration (S+E), atorvastatin and ezetimibe co-administration (A+E), rosuvastatin and ezetimibe co-administration (R+E), rosuvastatin monotherapy, and atorvastatin monotherapy. For each baseline HET, we used analysis of covariance (ANCOVA) to estimate the least squares mean (LSM) difference in the percentage change from baseline in LDL-C between switchers and non-switchers, and logistic regression to estimate the odds ratio of attaining the LDL-C goal (<3 mmol/L for primary prevention and <2 mmol/L for secondary prevention, by JBS2) at follow-up. Propensity score adjusted analyses were conducted to reduce selection bias., Findings: 30,148 patients met the eligibility criteria with 83.8% received atorvastatin, 9.5% rosuvastatin and 2.6% S/E and S+E combined. 89.1% of patients switching from atorvastatin switched to an equivalent or higher dose of simvastatin (dose equivalency was determined by relative efficacy of one statin to other statins), while 100% of those switching from simvastatin/ezetimibe and 96.8% of those switching from rosuvastatin switched to lower than equivalent dose of simvastatin. Compared to non-switchers, the adjusted least squares mean differences in the percentage change in LDL-C levels from baseline were 18.74% (p = 0.0003), 16.73% (p < 0.0001), and -0.11% (p = 0.9044) when switching from simvastatin/ezetimibe, rosuvastatin, and atorvastatin, respectively. The odds of LDL-C goal attainment at follow-up among switchers from simvastatin/ezetimibe, rosuvastatin, and atorvastatin were 0.40 (95% CI: 0.23-0.70), 0.36 (95% CI: 0.26-0.51) and 1.03 (95% CI: 0.92-1.15) relative to non-switchers respectively., Implications: Among the high risk CVD population in UK, switching to simvastatin from HET, especially rosuvastatin and simvastatin/ezetimibe, resulted in an increase in LDL-C levels and lower goal attainment. These historical data reinforce the appropriateness of the changes in the new Joint British Guideline (JBS3) which no longer recommends starting simvastatin 40 mg., (Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.)

Purpose: Platelet-function suppression with antiplatelet therapy is effective in preventing and treating cardiovascular disease. Clopidogrel is a thienopyridine derivative that blocks platelet activation by adenosine diphosphate receptor binding. This study demonstrates the effects of generic clopidogrel bisulfate in comparison to branded clopidogrel bisulfate in patients with acute coronary syndromes., Methods: This prospective, 2-arm, single-center, open-label trial used 1:1 randomization to assign patients to receive generic or branded clopidogrel bisulfate. Patients with unstable angina or non-ST-segment elevation myocardial infarction and scheduled to undergo coronary angiography were enrolled. Platelet function was measured with a P2Y12 assay and reported in P2Y12 reaction units (PRU) and aspirin reaction units (ARU) after randomization. Platelet function was measured at 2, 4, 8, and 24 hours after 600-mg clopidogrel loading. The clinical outcome was checked at 1 month after coronary angiography., Findings: Ninety-five patients were enrolled and randomized to the generic or branded group. Ninety patients (62 men [69%], 28 women [31%]; mean age, 58 years) completed the study protocol. The clinical characteristics were similar between the 2 groups. The difference in the baseline PRU measurements between the generic and branded groups was not significant (274.8 [59.7] vs 285.4 [62.4], respectively; P = 0.414). There were significant differences in 2-hour PRU (231.1 [71.3] vs 266.9 [67.4]; P = 0.017) and 4-hour PRU (227.3 [80.4] vs 265.7 [71.0]; P = 0.020); however, 24-hour PRU (200.5 [82.1] vs 220.6 [75.8]; P = 0.253) was similar. No death, myocardial infarction, target lesion revascularization, stent thrombosis, or Thrombolysis in Myocardial Infarction-defined major bleeding complications were reported during in-hospital stay or 1-month follow-up., Implication: In patients with ACS, loading of generic clopidogrel bisulfate was associated with an antiplatelet effect comparable to that of branded clopidogrel bisulfate. ClinicalTrials.gov identifier: NCT02060786., (Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.)

Background: Pitavastatin, a fully synthetic β-hydroxy-β-methylglutaryl-coenzyme A reductase inhibitor, is potent for the treatment of primary hyperlipidemia and mixed dyslipidemia. Recently, the original product and some generic products of pitavastatin calcium have become available in China. However, the intrasubject variability and interchangeability of this newly developed generic product and the branded innovator product have rarely been investigated in the Chinese population., Purpose: The aim of this study is to develop and compare the scaled-average, population, and individual bioequivalence (BE) of pitavastatin calcium tablets in healthy Chinese volunteers. This study will be used to allow for the interchangeability (switchability and prescribability) of the 2 products in clinical medication in China., Methods: A single-dose, reference-replicated, 3-period crossover BE study was conducted in 36 healthy male volunteers. Plasma samples were collected before and after oral administration of 2-mg test or reference tablets. A LC-MS/MS method was used to determine the concentration of pitavastatin calcium. A noncompartmental method was used to investigate the pharmacokinetic parameters. The ANOVA and 90% CIs of ln(AUC0-t) and ln(Cmax) were used for statistical analysis of scaled-average BE. A nonparametric test (Wilcoxon signed rank test) was performed to Tmax. The analyses of population BE and individual BE were used to assess the switchability and prescribability of the 2 products., Findings: Thirty-six volunteers were enrolled in this clinical research; 33 volunteers completed the 3 treatment periods. The mean (SD) relative bioavailability calculated from the ratios (T/R) of AUC0-t was 101.3% (19.7%). The mean ln(AUC0-t) and ln(Cmax) were 98.64 (90% CI, 93.44-104.13) and 98.68 (90% CI, 91.88-105.99) within previously stipulated ranges recommended by the US Food and Drug Administration and the China Food and Drug Administration (CFDA). The intrasubject %CVs of AUC0-t and Cmax were 12.0% and 18.0% for the reference tablet and 13.0% and 17.0% for the test tablet. No significant differences were found among Tmax (0.742 ± 0.276, 0.674 ± 0.202, and 0.689 ± 0.226, respectively) for reference tablet 1, reference Supplemental Table II in the online version at 10.1016/j.clinthera.2014.06.21, and test tablet by a Wilcoxon test (P > 0.05). For ln(AUC0-t) and ln(Cmax), the statistical test-reference ratios were 99.13% and 98.95%, respectively. After inspecting the results for reference and mixed scaling, all the upper confidence limits were <0; therefore, population and individual BE were given., Implications: In the healthy Chinese males, the generic and branded name tablets of pitavastatin calcium are bioequivalent at the rate and extent of absorption after a comparison of scaled-average, population, and individual BE and thus may be used interchangeably. Both the formulations are generally well tolerated. Chinese Clinical Trial identifier: ChiCTR-TTRCC-13003973., (Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.)

Background: Sulfadoxine/pyrimethamine fixed-dose combination (FDC) tablet is the long-acting portion of the antimalaria product Artecospe(®), coblister containing artesunate tablets plus sulfadoxine/pyrimethamine FDC tablets. This study was conducted to support the efficacy and tolerability of the sulfadoxine/pyrimethamine FDC tablet in the World Health Organization's (WHO) Prequalification of Medicines Programme, as well as to obtain marketing authorization in China., Objective: The aim of the present study was to compare the pharmacokinetic profiles between a new generic and the branded reference formulation of sulfadoxine/pyrimethamine FDC tablets, and to assess the bioequivalence of the 2 products in healthy Chinese volunteers., Methods: This single-dose, open-label, randomized, parallel-group study was conducted in healthy Chinese male volunteers who were randomly assigned (1:1) to receive a single 1500/75-mg dose (3 × 500/25-mg tablets) of either the test or reference formulation after a 12-hour overnight fast. Seventeen blood samples were obtained over a 168-hour interval, and plasma concentrations of sulfadoxine and pyrimethamine were determined by 2 separate validated liquid chromatography-isotopic dilution mass spectrometry methods. Pharmacokinetic properties (C(max), AUC(0-72), AUC(0-168), and T(max)) were calculated and analyzed statistically. The 2 formulations were to be considered bioequivalent if 90% CIs for the log-transformed ratios of C(max) and AUC(0-72) were within the predetermined bioequivalence range of 80% to 125%, in accordance with the guidelines of WHO and China's Food and Drug Administration (FDA). Tolerability was evaluated throughout the study by vital signs, physical examinations, clinical laboratory tests, 12-lead ECGs, and subject interviews on adverse events (AEs)., Results: Forty-six healthy subjects completed the study. The mean values of sulfadoxine C(max) (183.07 and 165.15 mg/L), AUC(0-72) (11,036.52 and 10,536.78 mg/L/h), and AUC(0-168) (22,247.05 and 21,761.02 mg/L/h) were not significantly different between the test and reference formulations, respectively. The same was true for pyrimethamine (0.55 and 0.58 mg/L, 29.85 and 31.44 mg/L/h, and 56.18 and 59.27 mg/L/h, respectively). The 90% CIs for the log-transformed ratios of C(max), AUC(0-72), and AUC(0-168) of both sulfadoxine (105.4%-116.6%, 99.3%-110.6%, and 96.4%-108.1%) and pyrimethamine (88.8%-100.9%, 89.5%-101.0%, and 88.3%-101.6%) were within the acceptance limits for bioequivalence. A total of 7 mild AEs were reported in 7 subjects (15.2%)., Conclusions: The findings from this single-dose (1500/75-mg) study suggest that the test and reference formulations of sulfadoxine/pyrimethamine FDC 500/25-mg tablet have similar pharmacokinetic profiles both in terms of rate and extent of absorption. The formulations met WHO's and China's FDA regulatory criteria for bioequivalence in these healthy Chinese volunteers under fasting conditions. Both formulations were generally well-tolerated., (Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.)

Background: Sildenafil citrate (SIL) was the first oral drug registered in Mexico for the treatment of erectile dysfunction. However, succinct pharmacokinetic data are available in the Mexican population., Objective: The goals of the present work were: (1) to design a specific method to quantify SIL plasma levels by using UPLC-MS/MS; (2) to compare oral SIL bioavailability in Mexican men with pharmacokinetic data in other populations; (3) to fulfill local regulatory requests; and (4) to describe the relative tolerability of a new 50-mg chewable tablet., Methods: This was a randomized, single-dose, 3-period, 6-sequence crossover study in healthy male volunteers. In each period, subjects received single oral doses of 100 mg of sildenafil (1 commercial [reference(⁎)], 1 generic [test 1(†)], or 2 chewable generic tablets [test 2(‡)]), with a 4-day washout period between each dose. Serial blood samples were collected for up to 24 hours. SIL was measured in heparinized plasma by using a validated UPLC-MS/MS method. Pharmacokinetic parameters included C(max), T(max), AUC(0-24), and AUC(0-∞). Bioequivalence was established if 90% CIs for mean test:reference ratios of log-transformed C(max) and AUC fell within the range of 0.80 to 1.25. Tolerability was assessed on the basis of a clinical interview with the subject and monitoring of vital signs., Results: Demographic data showed a homogeneous population. Validation of analytical method proved to be linear within the range of 1 to 1000 ng/mL, with selectivity, accuracy, and precision. 90% CIs for test 1:reference ratios were 86.52 to 113.56, 94.75 to 108.84, and 94.97 to 108.82 for the logarithm parameters C(max), AUC(0-24), and AUC(0-∞), respectively. The 90% CIs for the test 2:reference ratios were 82.14 to 107.24, 98.26 to 112.56, and 99.19 to 113.34 for C(max), AUC(0-24), and AUC(0-∞). Regarding relative tolerability, slight cephalea was the most common adverse effect., Conclusions: The developed analytical method was validated in compliance with local requirements and was useful for sildenafil measurement. This single-dose study under fasting conditions suggests that both test products met the Mexican regulatory criteria for assuming bioequivalence in these healthy, male Mexican volunteers. The clinical data suggest that the chewable tablets were well tolerated by volunteers., (Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.)

Background: Currently, levodopa administered with decarboxylase inhibitors is the gold standard for the management of the motor symptoms of Parkinson's disease, a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. In Argentina, only 1 commercial product is available with such composition; this study was contracted by the manufacturer to comply with new generic product regulations., Objective: The aim of this study was to evaluate the fasting bioavailability of a new generic formulation of levodopa 200 mg/benserazide 50 mg tablets (test) and compare this generic formulation with the branded formulation (reference) to meet regulatory criteria for marketing the test product in Argentina., Methods: A randomized-sequence, open-label, 2-period, crossover study was conducted between August and October 2009 in healthy Caucasian volunteers (n = 24; 18 males, aged 21 to 42 years, with a body mass index ranging from 19.7 to 26.0 kg/m(2)) in the fasted state. A single oral dose of the test or reference formulation was administered, and after a 7-day washout period, the other formulation was given. Blood samples were collected at baseline and at 10, 20, 30, 40, 50, 60, 70, 80, 90, and 105 minutes and 2, 2.5, 3, 3.5, 4, and 6 hours after dosing. Levodopa plasma concentrations were measured by high-performance liquid chromatography with electrochemical detection, without stereo-specificity assessment. The formulations were considered bioequivalent if the 90% CI of the geometric mean ratios (test/reference) for the C(max) and AUC(0-t) of levodopa were within the 0.8 to 1.25 range. Adverse events were monitored throughout the study, based on clinical parameters and patient reports., Results: The geometric means (90% CI) of the C(max) for the test and reference formulations were 2462.02 (2312.06-3492.40) and 2542.85 (2394.49-3231.29) ng/mL, respectively; the AUC(0-t) was 3878.04 (3623.88-5393.09) and 3972.10 (3765.88-5393.02) ng/mL/h, respectively; and the AUC(0-∞)was 4610.37 (4315.71-6315.70) and 4728.96 (4502.17-6828.26) ng/mL/h, respectively. There were no significant differences in pharmacokinetic parameters between the 2 formulations. The test:reference ratios for C(max), AUC(0-t), and AUC(0-∞) were 96.82% (90% CI, 83.87-111.77), 97.63% (90% CI, 85.95-110.91), and 97.49% (90% CI, 84.09-113.02), respectively. No clinically significant adverse events were reported; this finding is probably the result of subjects not believing that their side effects were severe enough to be reported and not because of a genuine and absolute lack of predictable side effects., Conclusions: In this single-dose study, the test formulation of levodopa/benserazide tablets met the Argentinean criterion for bioequivalence to the reference formulation. (www.clinicaltrials.gov: NCT01327261)., (Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.)

Background: The proprietary formulation of fluoxetine hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. Pharmacokinetic studies investigating the bioequivalence of generic and branded formulations are needed to market generic fluoxetine in China., Objective: The aim of this study was to compare the bioavailability and tolerability of the proposed generic formulation with the established reference formulation of fluoxetine hydrochloride 20 mg in a fasting, healthy Chinese male population., Methods: This 10-week, open-label, randomized-sequence, single-dose, 2-period crossover study was conducted in healthy native Han Chinese male volunteers. Eligible subjects were randomly assigned in a 1:1 ratio to receive a single 20-mg dose of the test or reference formulation, followed by a 35-day washout period and administration of the alternate formulation. Doses were administered after a 12-hour overnight fast. For analysis of pharmacokinetic properties (including C(max), T(max), AUC(0-t), AUC(0-∞), and t(½)), blood samples were obtained over a 672-hour period after dosing. Plasma concentrations of fluoxetine and its active metabolite, norfluoxetine, were analyzed using a validated LC-MS/MS method. The formulations were to be considered bioequivalent if the ln-transformed ratios (test/ reference) of C(max) and AUC were within the predetermined bioequivalence range of 80% to 125%, as established by the US Food and Drug Administration, and if the P values were <0.05 for the 90% CIs. Signs and symptoms of adverse effects of fluoxetine hydrochloride such as nausea, vomiting, insomnia, somnolence, anxiety, and nervousness, as well as any untoward effects, were collected using a daily written questionnaire and recorded by the study physicians. Tolerability was assessed using monitoring of vital signs, physical ex- amination, ECG, and routine blood and urine tests, along with blood biochemical tests, at the start as well as at the end of the study., Results: Twenty-four subjects were enrolled and completed the study (mean [SD] age, 24.4 [2.3] years [range, 20-30 years]; weight, 63.6 [8.5] kg [range, 51.2-86.8 kg]; height, 1.72 [0.07] m [range, 1.57-1.91 m]). The AUC values for fluoxetine were not consistent with a normal distribution, reflecting the existence of 2 different populations (poor and extensive metabolizers). Data from the one poor metabolizer were excluded from the pharmacokinetics data summarized. In extensive metabolizers, the mean (SD) C(max) for fluoxetine with the test formulation was 11.786 (3.459) ng/mL and T(max) was 5.48 (2.06) hours. With the reference formulation, the corresponding values were 11.754 (3.292) ng/mL and 6.26 (5.77) hours, respectively. The t(½) values with the test and reference formulations were 30.86 (7.61) and 30.96 (6.91) hours, respectively. For norfluoxetine, mean C(max) with the test formulation was 14.177 (4.957) ng/mL and T(max) was 58.48 (31.67) hours; the corresponding values for the reference formulation were 13.828 (4.838) ng/mL and 57.91 (25.75) hours. The t(½) values with the test and reference formulations were 130.91 (42.04) and 128.79 (52.72) hours, respectively. For fluoxetine, the 90% CIs (in extensive metabolizers only) for the In-transformed C(max), AUC(0-168), and AUC(0-∞) were 92.0% to 108.4%, 95.7% to 110.3%, and 97.4% to 111.3%, respectively (all, P < 0.001). For norfluoxetine, the 90% CIs for the ln-transformed C(max), AUC(0-672), and AUC(0-∞) were 93.7% to 110.7%, 98.9% to 111.4%, and 98.8% to 110.9% (all, P < 0.001). No period or sequence effects were observed for any pharmacokinetic variable in the extensive metabolizers. No adverse events were reported by the volunteers or found with results of clinical laboratory testing., Conclusions: This single-dose study found that the test and reference formulations of fluoxetine hydro- chloride met the regulatory criteria for bioequivalence in these fasting, healthy Chinese male volunteers. Both formulations appeared to be well tolerated., (Copyright © 2010 Excerpta Medica Inc. All rights reserved.)

Background: Data regarding the pharmacokinetic properties of risperidone in the Thai population are limited. A new generic tablet formulation was recently developed, but bioequivalence research is necessary to obtain marketing authorization for it in Thailand., Objective: The aim of this study was to evaluate and compare the pharmacokinetic properties of risperidone and its active metabolite, 9-hydroxyrisperidone (which reportedly contributes to the drug's pharmacodynamic effects), in a newly developed generic tablet formulation (test) and a branded formulation (reference) in healthy, fasting, male Thai volunteers., Methods: A single-dose, randomized-sequence, double-blind, 2-way crossover design was used in this study. The study took place from October 21 through November 28, 2007. After a ≥10-hour overnight fast, volunteers were orally administered one 2-mg risperidone tablet, either the test formulation (Condrug International Company, Ltd.) or the reference formulation-according to the randomization schedule-followed by a 14-day washout period and administration of the alternate formulation. Blood samples were collected over a period of 96 hours. Risperidone and 9-hydroxyrisperidone plasma concentrations were simultaneously determined using a validated HPLC/ion trap mass spectrometry method. The plasma concentration-time curves of the active moiety, risperidone, and 9-hydroxyrisperidone were generated for each volunteer, from which the C(max), T(max), AUC₀₋(last), AUC₀₋(∞), and t(½) were determined using noncompartmental analysis. The effects of formulation, period, sequence, and subject (within sequence) on pharmacokinetic parameters were analyzed using ANOVA. According to regulatory requirements set forth by Thailand, the Association of Southeast Asian Nations, and the US Food and Drug Administration, products meet the criteria for bioequivalence if the 90% CIs of the treatment ratios for C(max) and AUC are within the range of 0.80 to 1.25. Tolerability was assessed by patient interview, monitoring vital signs (ie, resting blood pressure, heart rate, body temperature), physical examination, and laboratory tests (ie, urinalysis, hematology, blood chemistry) before and after the study., Results: A total of 22 Thai male volunteers (mean [SD] age, 28.18 [8.27] years [range, 20.62-44.19 years]; weight, 62.43 [4.76] kg [range, 55.03-76.02 kg]; and body mass index, 21.76 [2.07] kg/m² [range, 18.9924.91 kg/m²]) completed the study. The mean (SD) relative bioavailabilities of test to reference formulations determined from AUC of the active moiety, risperidone, and 9-hydroxyrisperidone were 1.06 (0.18), 1.07 (0.29), and 1.04 (0.17), respectively. The ANOVA suggested no statistically significant effect of formulation, period, or sequence on the studied pharmacokinetic parameters of the active moiety, risperidone, or 9-hydroxyrisperidone. The 90% CIs for the natural logarithm-transformed ratios of C(max), AUC₀₋(last), and AUC₀₋(∞) were as follows: for active moiety, 0.94 to 1.03, 0.98 to 1.11, and 0.98 to 1.10, respectively; for risperidone, 0.90 to 1.10, 0.96 to 1.13, and 0.96 to 1.14, respectively; and for 9-hydroxyrisperidone, 0.91 to 1.03, 0.97 to 1.10, and 0.96 to 1.09, respectively. All met the criteria for bioequivalence. The most commonly reported adverse events (AEs) were somnolence (100.0%), orthostatic hypotension (13.6%), headache (4.5%), and syncope (2.3%). AEs were mild and disappeared within 1 day. No volunteers withdrew from the study because of AEs., Conclusions: The single-dose pharmacokinetic data in this small, all-male, selected sample of fasting, healthy volunteers met Thailand's regulatory criteria for assuming bioequivalence of the tested generic and reference 2-mg risperidone tablets. Both formulations were well tolerated., (Copyright © 2010 Excerpta Medica Inc. All rights reserved.)

Background: In Bangladesh, a number of generic oral formulations of esomeprazole are marketed. Study of the relative bioavailability of these generic formulations has yet to be conducted in a Bangladeshi population., Objectives: The aims of this study were to assess the relative bioavailability and pharmacokinetic properties of 2 formulations (test and reference) of esomeprazole 40 mg., Methods: This open-label, randomized, 2-way crossover study was conducted in healthy Bangladeshi male subjects in compliance with the Declaration of Helsinki and International Conference on Harmonisation guidelines. Subjects were randomly assigned to receive the test formulation followed by the reference formulation or vice versa, as a single dose of esomeprazole 40 mg after a 12-hour overnight fast. A washout period of 1 week was maintained between treatments. Following oral administration, blood samples were collected at 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 5, 7, 9, and 12 hour(s) after dosing and analyzed for esomeprazole concentrations using a validated HPLC method. Pharmacokinetic parameters, including C(max), AUC(0-12), and AUC(0-infinity), were determined with a non-compartmental method. The formulations were to be considered bioequivalent if the natural log (ln)-transformed ratios of the pharmacokinetic parameters were within the predetermined bioequivalence range of 80% to 125%, according to the US Food and Drug Administration (FDA) requirement. The within- and between-group differences were examined using ANOVA. Tolerability was assessed by monitoring vital signs and conducting subject interviews regarding adverse events. Interviewers were not blinded to study design., Results: A total of 24 nonsmoking, healthy, Bangladeshi male subjects (mean [SD] age, 22.8 [2.22] years [range, 20-29 years]; weight, 64.7 [6.9] kg [range, 55-79 kg]; height, 1.69 [0.05] m [range, 1.63-1.82 m]; and body mass index, 22.39 [2.16] kg/m(2) [range, 18.99-27.34 kg/m(2)]) were enrolled. From serum data, the mean (SD) values for the test and reference products were as follows: 5.26 (1.57) and 5.54 (2.94) micromol/L for C(max); 2.53 (0.67) and 2.07 (0.65) hours for T(max); 15.74 (6.50) and 16.68 (6.77) micromol/L/h for AUC(0-12); and 17.15 (7.58) and 18.26 (7.31) micromol/L/h for AUC(0-infinity), respectively. The mean T(max) was found to be significantly different between the test and reference formulations (2.53 [0.67] vs 2.07 [0.65] hours, respectively; P < 0.05). The point estimates (90% CI) for the test/reference ratios of the In-transformed AUC(0-infinity) and C(max) were 92.92% (84.02%-102.76%) and 102.36% (85.96%-121.90%), respectively, which were within the FDA-accepted limits for assuming bioequivalence. No adverse events were reported by the volunteers during the study., Conclusion: This single-dose study found that the test and reference formulations of esomeprazole 40 mg met the FDA regulatory criteria for assuming bioequivalence in these healthy, fasting Bangladeshi male volunteers. A significant difference was found in T(max) between the 2 formulations. Both formulations were well tolerated in the studied population., (2010 Excerpta Medica Inc. All rights reserved.)

Background: Atorvastatin calcium is a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor indicated for the prevention of cardiovascular disease and for the treatment of dyslipidemia. Information on the pharmacokinetics of atorvastatin in a Chinese population is lacking, and regulatory requirements necessitate a bioequivalence study for the marketing of a generic product in China., Objective: The aim of the present study was to assess the pharmacokinetics and bioequivalence of a test and branded reference formulation of atorvastatin calcium 10-mg tablets in healthy fasted Chinese male volunteers., Methods: This was a single-dose, randomized-sequence, open-label, 2-period crossover study with a 2-week washout period between doses. Healthy Chinese males were randomly assigned to receive 20 mg of either the test or reference formulation, and 13 blood samples were obtained over a 48-hour interval. Plasma concentrations of parent atorvastatin and ortho-hydroxy-atorvastatin (primary active metabolite) were simultaneously determined using a validated liquid chromatography-isotopic dilution mass spectrometry method. Pharmacokinetic parameters, including C(max), T(max), t((1/2)), AUC(0-t), and AUC(0-infinity)), were calculated. The 2 formulations were to be considered bioequivalent if 90% CIs for the log transformed ratios of AUC and C(max) of atorvastatin were within the predetermined bioequivalence range (0.80-1.25 for AUC and 0.70-1.43 for C(max)) as established by the State Food and Drug Administration of China. Tolerability was evaluated throughout the study by vital signs monitoring, physical examinations, 12-lead ECGs, and subject interviews on adverse events (AEs)., Results: A total of 66 subjects were assessed for inclusion; 20 were excluded prior to study initiation. Of the 46 healthy subjects (mean [SD] age, 24.1 [2.5] years; height, 170.8 [5.1] cm; weight, 64.6 [6.4] kg; body mass index (BMI), 22.1 [1.7] kg/m(2)) who completed the study, 45 subjects (mean [SD] age, 24.1 [2.5] years; height, 171.1 [4.9] cm; weight, 64.8 [6.3] kg; BMI, 22.1 [1.7] kg/m(2)) were included in the pharmacokinetic and bioequivalence analyses; 1 subject was excluded from these analyses because he mistakenly received the same formulation in both periods. No period or sequence effect was observed. The mean values of C(max), AUC(0-t), and AUC(0-infinity)) for the test and reference formulations of atorvastatin (8.78 and 10.76 ng/mL, 38.22 and 40.02 ng/mL/h, 42.73 and 44.51 ng/mL/h, respectively) and ortho-hydroxy-atorvastatin (5.78 and 5.77 ng/mL, 47.32 and 48.47 ng/mL/h, 52.36 and 53.14 ng/mL/h) were not significantly different. The 90% CIs for natural log-transformed ratios of C(max), AUC(0-t), and AUC(0-infinity)) of both atorvastatin (0.73-0.91, 0.92-1.02, and 0.91-1.01, respectively) and ortho-hydroxy-atorvastatin (0.83-1.05, 0.92-1.02, and 0.93-1.02) were within the bioequivalence acceptance limits. Three subjects (6.5%) reported a total of 4 mild AEs (1 abdominal discomfort and 3 venipuncture syncope), which were not considered to be associated with administration of the study drug., Conclusions: This single-dose (20 mg) study found that the test and reference formulations of atorvastatin calcium 10-mg tablet met the regulatory definition for assuming bioequivalence in these healthy fasted Chinese male volunteers. Both formulations were generally well tolerated in the population studied. Chinese National Registry Code: 2007L02512., (2010 Excerpta Medica Inc. All rights reserved.)

Background: Losartan is a nonpeptide angiotensin II receptor antagonist used as an antihypertensive agent. The relative bioavailability of a newly developed tablet compared with an established branded formulation has not been reported in a Chinese population., Objective: To meet the requirements for marketing a new generic product, the study was designed to compare the pharmacokinetic parameters and relative bioavailability of a new generic losartan potassium 50-mg tablet (test formulation) with a branded 50-mg tablet (reference formulation) in healthy Chinese male volunteers., Methods: A single-dose, randomized-sequence, openlabel, 2-way crossover study was conducted in healthy Chinese male volunteers. Eligible participants were randomly assigned in a 1:1 ratio to receive a single 50-mg tablet of the test or reference formulation, followed by a 1-week washout period and then administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Plasma samples were collected over 36 hours. Tolerability was evaluated by recording adverse events (AEs) and monitoring vital signs, ECGs, and laboratory tests at baseline and at completion of the study. Plasma concentrations of losartan and its active metabolite (EXP3174) were analyzed by LC-MS/MS. Pharmacokinetic parameters, including C(max), AUC(0-36), and AUC(0-infinity), were calculated. If the 90% CIs for the log-transformed values of AUC were within 80% to 125%, and that of C(max) was within 70% to 143%, the 2 products would be considered bioequivalent according to the guidelines of the US Food and Drug Administration and the State Food and Drug Administration of China., Results: Twenty-seven healthy Chinese male volunteers participated in this study (mean [SD] age, 24.5 [2.3] years [range, 20-29 years]; weight, 64.6 [4.0] kg [range, 60.0-75.0 kg]; height, 172.2 [4.8] cm [range, 165.0183.0 cm]; and body mass index, 21.8 [1.2] kg/m(2) [range, 20.0-25.0 kg/m(2)]). One volunteer (3.7%) experienced an AE (microscopic hematuria) after administration of the test formulation. This resolved spontaneously after 10 days and was considered by the investigator as mild; the relationship with the study drug was uncertain. No serious AEs were reported. Both formulations were associated with significant reductions in systolic and diastolic blood pressure and significant increases in heart rate compared with baseline values (all, P < 0.05). No period, formulation, or sequence effects were observed for any pharmacokinetic parameter, except for a significant subject effect. For parent losartan, the 90% CIs for the ratios (test/reference) of C(max), AUC(0-36), and AUCAUC(0-infinity) were 83.65% to 113.36%, 89.79% to 98.25%, and 90.95% to 99.55%, respectively. For the metabolite EXP3174, the 90% CIs for the ratios of C(max), AUC(0-36), and AUCAUC(0-infinity) were 93.49% to 103.61%, 96.79% to 104.09%, and 97.06% to 105.83%. Both C(max) and AUC met the predetermined criteria for assuming bioequivalence. The relative bioavailability of the test formulation to the reference formulation was 93.92% for losartan and 100.40% for EXP3174., Conclusions: In this small study in healthy Chinese male volunteers, a single 50-mg oral dose of a losartan potassium tablet (test formulation) met the regulatory criteria for assuming bioequivalence to the established reference formulation. Both formulations were well tolerated., (2010 Excerpta Medica Inc. All rights reserved.)

Background: Valsartan is a selective angiotensin II type 1 receptor blocker indicated for the treatment of hypertension. Although the bioavailability and pharmacokinetic 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 assigned 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 samples were collected at prespecified times over a period of 24 hours after administration. An HPLC method was used for the estimation of plasma valsartan concentrations. A noncompartmental method was employed to determine the pharmacokinetic properties (C(max), T(max), AUC(0-t), AUC(0-infinity), and t(1/2)) to test for bioequivalence. The predetermined regulatory range of 90% CI for bioequivalence was 80% to 125%. Tolerability was assessed using physical examination, including 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 reference formulation, the 90% CIs of the least squares mean test/reference ratios of C(max), AUC(0-t), and AUC(0-infinity) 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., Conclusions: In this single-dose study in a small sample of healthy Indian male subjects, test formulation B of valsartan 160 mg was considered bioequivalent to the reference formulation as per predetermined regulatory criteria, whereas test formulation A was not. All 3 formulations were well tolerated., (Copyright 2010 Excerpta Medica Inc. All rights reserved.)

Background: Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is an immunosuppressive agent indicated for the prophylaxis of organ rejection in allogeneic kidney, heart, or liver transplant recipients. The European regulatory authorities require bioequivalence studies for the marketing of generic products., Objective: The aim of this study was to assess the bioequivalence of a generic (test) and branded (reference) formulation of MMF 500 mg and MPA., Methods: This single-center, single-dose, randomized, open-label, 4-way crossover study was conducted at Anapharm's Clinical Research Facility, Québec, Québec, Canada. Healthy volunteers aged 18 to 55 years were eligible. Subjects were assigned to receive, in randomized order, a single dose of the test and reference formulations of MMF 500 mg under fasting conditions. Because the study design was 4-way replicate, there were 2 test periods and 2 reference periods. The 4 study periods were each separated by a 14-day washout period. Blood samples were collected over a period of 12 hours after administration for the determination of MMF pharmacokinetic properties, and over 48 (+/-0.5) hours, for MPA properties. Concentrations of the analytes were determined by reverse LC and detected using LC-MS/MS. Pharmacokinetic parameters were calculated from MMF and MPA concentration data using noncompartmental analysis. C(max) and AUC(0-t) were the primary evaluation criteria, while AUC(0-infinity) was a secondary parameter. The drugs were to be considered bioequivalent if the 90% CIs for the test/reference ratios of natural logarithm-transformed values of these parameters (obtained using ANOVA) were between 80% and 125%, per European regulations for bioequivalence. Tolerability was monitored using physical examination, including vital sign measurements, laboratory analysis, and adverse-events (AE) monitoring (including patient interview)., Results: A total of 103 subjects were enrolled (64 men, 39 women; 101 white, 2 black; mean [SD] age, 38 [10] years; weight, 68.2 [9.1] kg). The 90% CIs were as follows: MMF, C(max), 85.94% to 106.63%; AUC(0-t), 91.94% to 102.20%; and AUC(0-infinity), 93.15% to 105.48%; MPA, C(max), 92.03% to 105.82%; AUC(0-t), 97.42% to 100.59%; and AUC(0-infinity), 96.96% to 100.90%. These values met with the regulatory definition of bioequivalence. A total of 148 AEs were reported (68 in subjects who received the test treatment and 80 in subjects who received the reference treatment). The most commonly reported AEs were procedural pain (13/102 [12.7%] and 10/101 [9.9%] with the test and reference formulations, respectively), procedural site reaction (12 [11.8%] and 4 [4.0%]), and somnolence (7 [6.9%] and 14 [13.9%])., Conclusions: The generic and branded formulations of MMF 500 mg met the European regulatory criteria for assuming bioequivalence, based on the rate and extent of absorption of a single dose under fasting conditions. Both formulations were well tolerated in these healthy volunteers., (Copyright 2010 Excerpta Medica Inc. All rights reserved.)

Background: Piroxicam is an NSAID indicated for the treatment of rheumatoid diseases. Although there are generic formulations of oral piroxicam marketed in Mexico, a literature search did not identify published data concerning the bioavailability of these formulations in the Mexican population., Objectives: The aims of this study were to determine the bioequivalence of a generic (test) and a reference formulation of oral piroxicam 20 mg and to generate data regarding the oral bioavailability of this drug in a Mexican population., Methods: This single-dose, randomized-sequence, open-label, 2-period crossover study was conducted in healthy Mexican adult volunteers. Subjects were randomly assigned to receive the test formulation followed by the reference formulation, or vice versa, with a 15-day washout period between doses. Study drugs were administered after a 10-hour overnight fast. For pharmacokinetic analysis, blood samples were drawn at 0 (baseline), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, and 168 hours after administration. Plasma concentrations of piroxicam were determined using HPLC. The test and reference formulations were to be considered bioequivalent if the 90% CIs for the geometric mean test/reference ratios were within a predetermined range of 80% to 125%. Tolerability was determined using clinical assessment, monitoring of vital signs, laboratory analysis, and subject interviews regarding adverse events (AEs)., Results: A total of 28 subjects were enrolled (15 men, 13 women; mean [SD] age, 24 [4] years [range, 19-35 years]; weight, 63.0 [8.9] kg [range, 47.5-81.9 kg]; height, 165 [10] cm [range, 149-179 cm]; and body mass index, 23.2 [1.4] kg/m(2) [range, 20.6-26.0 kg/m(2)]). The 90% CIs for piroxicam C(max), AUC(0-infinity), and AUC(0-infinity)) were 89.98% to 101.04%, 91.46% to 101.19%, and 93.51% to 105.86%, respectively. Thirteen subjects reported a total of 17 AEs during the study. None of the AEs were considered serious or related to the administered formulations. The most common AE was local postvenipuncture ecchymosis, reported in 8 subjects (28.6%)., Conclusions: In this small study in healthy Mexican adult subjects, a single 20-mg dose of the test formulation of orally administered piroxicam met the regulatory requirements to assume bioequivalence, based on the rate and extent of absorption. Both formulations were well tolerated. Mexican national registry code: CE-PEC.0875., (Copyright 2010. Published by EM Inc USA.)

Background: Platelet activation is a major component in the pathogenesis of coronary thrombosis and myocardial infarction. Thienopyridines, particularly clopidogrel, are highly effective in reducing in-stent thrombosis and functional inhibition of adenosine diphosphate-induced platelet activation., Objective: The aim of this study was to evaluate the bioequivalence of a new generic formulation of clopidogrel 75-mg tablets (test) and the available branded formulation (reference) to meet regulatory criteria for marketing the test product in Argentina., Methods: This was a randomized-sequence, open-label, 2-period crossover study conducted in healthy white volunteers in the fasted state. A single oral dose of the test or reference formulation was followed by a 7-day washout period, after which subjects received the alternative formulation. Blood samples were collected at baseline and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after dosing. Clopidogrel concentrations were determined using an LC-MS/MS method. The formulations were considered bioequivalent if the 90% CI of the geometric mean ratios (test:reference) for C(max) and AUC(0-last) were within the range from 80% to 125%. Adverse events were monitored throughout the study based on clinical parameters and patient reports., Results: Twenty-four volunteers (13 male, 11 female; mean [SD] age, 33.7 [5.2] years [range, 21-42 years]; weight, 72.4 [6.83] kg [range, 59-82 kg]) were enrolled in and completed the study. The geometric mean C(max) for the test and reference formulations was 877.76 and 913.49 pg/mL, respectively. The geometric mean AUC(0-t) was 1911.53 and 2053.09 pg . h/mL, and the geometric mean AUC(0-infinity)) was 2021.33 and 2188.25 pg . h/mL. The geometric mean ratios (test:reference) for C(max), AUC(0-t), and AUC(0-infinity)) were 96.09% (90% CI, 90.71-101.78), 93.10% (90% CI, 85.57-101.3), and 92.37% (90% CI, 85.06-100.31), respectively. There were no significant differences in pharmacokinetic parameters between groups. No adverse events were reported., Conclusion: In this single-dose study in healthy fasted volunteers, the test formulation of clopidogrel tablets met the US and Argentinian regulatory criterion for bioequivalence to the reference formulation.

Background: Bicalutamide is an oral nonsteroidal antiandrogen drug used during hormone ablation therapy for prostate cancer. A new generic formulation of bicalutamide has been developed., Objectives: This study was conducted to meet Korean and US regulatory requirements for the marketing of the generic 50-mg tablet formulation of bicalutamide. To this end, the pharmacokinetic properties of the new (test) formulation were compared with those of the currently marketed (reference) formulation. Tolerability was also evaluated., Methods: An open-label, randomized-sequence, single-dose, 2-period crossover study was conducted in healthy Korean male volunteers. Subjects received either the test or reference formulation of bicalutamide 50-mg tablets in the first period and crossed over to the alternative formulation in the second period. Serial blood samples for pharmacokinetic analysis were taken over 672 hours after dosing. Plasma concentrations of bicalutamide were measured by HPLC-MS/MS. Pharmacokinetic parameters, including AUC(0-672h), were determined by noncompartmental analysis. Log-transformed C(max) and AUC(0-672h) for the 2 formulations were compared. Tolerability was monitored based on laboratory tests, ECGs, vital signs, and physical examinations., Results: Of the 34 subjects initially enrolled, 33 completed the study. The mean (SD) age, height, and weight of participants were 25.8 (4.1) years, 173.6 (5.7) cm, and 68.9 (7.8) kg, respectively. The median T(max) was 36.0 hours for both formulations. The mean (SD) t(1/2), C(max), and AUC(0-672h) for the reference formulation were 135.4 (28.6) hours, 933.2 (169.2) microg/L, and 215,680.1 (48,753.4) microg x h/L, respectively. Corresponding values for the test formulation were 134.3 (30.7) hours, 946.7 (179.9) microg/L, and 221,708.8 (54,935.1) microg x h/L. The 90% CIs for the mean ratios (test/reference) of log-transformed C(max) and AUC(0-672h) were 0.97 to 1.06 and 0.98 to 1.07, respectively. Twelve adverse events were reported for each formulation, none of which were considered drug related in the test-formulation group and 4 of which were considered drug related in the reference-formulation group (3 cases of headache, 1 case of erythematous rash)., Conclusions: In this single-dose study in healthy Korean male subjects, the new formulation of bicalutamide 50-mg tablets met Korean and US regulatory criteria for assumption of bioequivalence with the currently marketed formulation. Both formulations were generally well tolerated, with no clinically relevant safety concerns., (Copyright 2009 Excerpta Medica Inc. All rights reserved.)

Background: Abciximab has been found to reduce major adverse cardiovascular events in patients with acute coronary syndrome (ACS). A previous study reported on the tolerability of biogeneric abciximab in patients with ACS. This formulation has been approved by the Korea Food and Drug Administration and is currently being marketed. Its ex vivo antiplatelet effect, however, has not been compared with that of branded abciximab., Objective: The purpose of the present study was to compare ex vivo antiplatelet activity, angiographic outcome, and bleeding complications between biogeneric and branded abciximab., Methods: This prospective, open-label, randomized, controlled study was conducted in Korea. Patients with ACS who underwent percutaneous coronary intervention (PCI) were randomized to receive biogeneric abciximab or branded abciximab. All patients received intracoronary unfractionated heparin 70 IU/kg and either biogeneric or branded abciximab 0.25 mg/kg IV bolus approximately 10 minutes before undergoing PCI, followed by a 0.125 microg/kg/min 12-hour infusion of the same formulation. The antiplatelet effect of both drugs was assessed at 3 time points (at baseline, and 10 minutes and 24 hours after the end of the bolus infusion) using a validated rapid platelet-function assay., Results: In total, 37 patients (30 men and 7 women; 19 receiving biogeneric abciximab and 18 receiving branded abciximab) were included. Patient demographics did not differ significantly between the 2 groups (16 men [84.2%] and 3 women [15.8%] in the biogeneric group vs 14 men [77.8%] and 4 women [22.2%] in the branded group; mean [SD] age, 65 [11] vs 60 [10] years; weight, 64.6 [8.7] vs 67.9 [10.1] kg, respectively). The bolus and the continuous infusion of the biogeneric and branded formulations achieved similar levels of platelet inhibition, with a mean (SD) inhibition of platelet aggregation >90% at 10 minutes after the end of the bolus infusion (94.7% [8.2%] vs 92.6% [16.9%], respectively; P = NS) and >65% at 24 hours (68.1% [9.8%] vs 70.9% [9.7%]; P = NS) compared with baseline. One thrombolysis in myocardial infarction major bleeding complication (retro-peritoneal hemorrhage) was reported in a patient who received biogeneric abciximab., Conclusion: There were no statistically significant differences in the antiplatelet effects of these 2 formulations in this small, selected population of Korean patients with ACS.

Background: Enoxaparin is a low-molecular-weight heparin (LMWH) indicated for antithrombosis. A branded formulation of subcutaneously administered enoxaparin has been available in China since 2000, and a generic formulation is being developed. In a literature search of the key term enoxaparin (publication years not restricted), no published data were identified regarding the pharmacokinetic profile of generic enoxaparin in Chinese subjects., Objective: The aim of this study was to determine the bioequivalence of generic (test) and branded (reference) formulations of enoxaparin 60 mg (6000 IU anti-Xa) SC in healthy subjects for the purpose of meeting regulatory requirements for marketing the generic formulation in China., Methods: Healthy Chinese male volunteers were eligible for this single-dose, randomized-sequence, open-label, 2-period crossover study. Participants were randomly assigned to receive the test and reference formulations of enoxaparin 60 mg SC injection (fasting state) in randomized order, with the 2 study periods separated by a 1-week washout period. For the assessment of anti-Xa and anti-IIa activities (surrogates used to describe the pharmacokinetic properties and bioavailability of LMWH), heparin clotting assay, and activated partial thromboplastin time (aPTT), blood samples were obtained before (hour 0; baseline) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours after study drug administration. The 2 formulations were to be considered bioequivalent if the 90% CIs for the logarithm-transformed values of C(max), T(max), AUC(0-t), and AUC(0-infinity) fell within the predetermined range of 80% to 125%. Tolerability was assessed by questioning subjects about symptoms of possible adverse events and using laboratory analysis (hematology, biochemistry, hepatic function tests, and urinalysis)., Results: Twenty-two subjects participated in the study (mean [SD] age, 21.10 [1.02] years [range, 19-23 years]; weight, 64.07 [5.93] kg [range, 54-75 kg]; and height, 173 [5] cm [range, 163-187 cm]). For anti-Xa activity, the 90% CIs of C(max), AUC(0-t), and AUC(0-infinity) were 100.4% to 106.7%, 100.7% to 105.8%, and 100.7% to 106.1%, respectively. Corresponding values for anti-IIa activity were 85.0% to 102.4%, 80.4% to 94.8%, and 80.1% to 96.0%. For the hepa-rin clotting assay, the values were 97.4% to 102.4%, 98.2% to 102.4%, and 96.0% to 102.7%; and for aPTT, values were 98.2% to 104.3%, 97.4% to 101.6%, and 93.4% to 117.4%. No adverse events were reported during the study., Conclusions: Based on the 90% CIs of anti-Xa and anti-IIa activities, heparin clotting assay results, and aPTT in these healthy Chinese male subjects, the test and reference formulations of enoxaparin 60 mg SC met the regulatory requirements for bio-equivalence. Both formulations were well tolerated.

Background: The proprietary form of topiramate is indicated in Mexico as an antiepileptic agent and in the prophylaxis of migraine headaches. However, before generic topiramate is placed on the market, pharmacokinetic studies investigating the bioequivalence of generic and branded formulations are needed., Objective: The aim of this study was to compare the bioequivalence and tolerability of a generic (test) and a branded (reference) formulation of topiramate 100 mg in healthy Mexican volunteers., Methods: This open-label, randomized-sequence, 2-period crossover study was conducted at Ipharma SA de CV, Monterrey, Mexico. Eligible subjects were healthy male Mexican volunteers aged 18 to 45 years. Participants were randomly assigned to receive 100 mg of the test or reference formulation, followed by a 3-week washout period and administration of the alternate formulation. Doses were administered after a 12-hour overnight fast. For analysis of pharmacokinetic properties, including C(max), AUC(0-t), and AUC(0-infinity), blood samples were obtained over a 144-hour period after dosing. The formulations were to be considered bioequivalent if calculations of a 90% CI for the ratio of the means of the measures for the test and reference formulations fell within bioequivalence limits, 80% to 125%, for logarithmic (log) transformation of C(max) and AUC, and if two 1-sided t tests showed P < 0.05. Tolerability was assessed using vital sign measurement (blood pressure, body temperature, heart rate, and respiratory rate), laboratory analysis (hematology, blood biochemistry, hepatic function, and urinalysis), and subject interview., Results: Twenty-eight men (mean age, 22.21 years [range, 18-28 years]; mean weight, 75.04 kg [range, 62-96 kg]; mean height, 177 cm [range, 163-192 cm]) were enrolled in this study, and 28 (14 each randomized to receive the test or reference formulation first) completed it. No period or sequence effects were observed. The 90% CIs for the log-transformed C(max), AUC(0-t) and AUC(0-infinity) were 94.70 to 112.05, 98.88 to 105.16, and 98.80 to 105.28, respectively (all, P < 0.05). No adverse events were reported by the volunteers or found on clinical laboratory testing during the study., Conclusions: This study did not find any statistically significant differences in C(max) or AUC values between the test and reference formulations of oral topiramate 100 mg in this population of healthy adult male Mexican volunteers. On that basis, and according to both the rate and extent of absorption, the test and reference formulations met the regulatory criteria for bioequivalence. Both formulations were well tolerated.

Background: Delayed esophageal transit or disintegration of oral bisphosphonate tablets before they enter the stomach may be of concern with respect to iatrogenic complications among patients receiving longterm treatment. Different formulations of generic bisphosphonate tablets meeting regulatory requirements may have substantial differences in pharmaceutical attributes from the branded product that may result in different characteristics during esophageal transit., Objective: The primary objective of this study was to evaluate and compare esophageal transit times and in vivo disintegration of 3 bisphosphonate formulations, one branded and the others generic, that are commercially available in Canada and the United Kingdom., Methods: This was a single-center, randomized, singleblind, 6-period crossover study in healthy postmenopausal women aged >50 years. Each subject received a single oral dose of a branded risedronate sodium 35-mg tablet and 2 generic formulations of alendronic acid 70-mg tablets (Novopharm Limited, Toronto, Canada, and Teva UK Limited, Morley, United Kingdom) in both the erect and semisupine (45 degrees ) positions. Although the products are labeled to be taken in the erect position, the semisupine position was included to simulate dosing in bedridden patients. Subjects took tablets with 30 mL of water in the morning after an overnight fast. The tablets were radiolabeled with technetium-99m ion-exchange resins to enable visualization and measurement of esophageal transit time and disintegration using a gamma camera. Dynamic scintigraphic images were obtained for a total of 10 minutes: 2 images per second for the first 30 seconds and 1 image every 15 seconds for 9.5 minutes. This was a mechanistic study and tolerability was not assessed., Results: The study was conducted in 20 healthy white female subjects with a mean age of 62 years (range, 51-77 years). The effect of body position was statistically significant (P = 0.043), with the estimated hazard ratio (HR) of 0.74 indicating longer transit time in the semisupine position relative to the erect position. There was a statistically significant difference in transit time among the 3 types of tablets (P = 0.007), with the Novopharm tablet (HR = 0.59; P < 0.001) and Teva tablet (HR = 0.71; P = 0.042) having longer transit times compared with the risedronate tablet. In 4 instances, the Novopharm tablet disintegrated and dispersed in the esophagus, once in the erect position and 3 times in the semisupine position., Conclusions: In these healthy female subjects, esophageal transit was delayed when the tablets were given in the semisupine position. The branded risedronate tablet had a significantly faster transit time than the 2 generic formulations of alendronate tested.

A series of tests was used to compare two formulations of the topical steroid beta-methasone dipropionate, Diprolene (manufactured by the innovator, Schering Corp.) and Topilene (a generic formulation, manufactured by Technilab). Cream and ointment formulations produced by both manufacturers were compared with respect to physicochemical characteristics, skin sensitivity in rabbits, and a vasconstrictor assay indicative of topical availability in man. The physicochemical tests revealed no differences between innovator and generic ointment formulations, whereas excipients varied widely for the cream products. Similarly, the ointment formulations were comparable on the skin sensitivity tests in rabbits, whereas the generic cream product was much more irritating than the innovator cream in this test. On the vasoconstrictor assay in man the ointments were comparable, while the activity of the generic cream was much lower (approximately 30%) than that of the innovator cream; this difference was highly statistically significant. The difference in vasoconstrictor activity of the two cream products is discussed in relation to the differences in their physicochemical properties. It is concluded that the generic Topilene cream is not interchangeable with the innovator Diprolene cream, and that both pharmacists and physicians should be very careful when substituting one topical steroid formulation for another.