Current Issue : July - September Volume : 2011 Issue Number : 3 Articles : 9 Articles
Imatinib is a highly selective inhibitor of tyrosine kinase used in the treatment of CML and GIST. However, the cost of the drug is prohibitive especially in the developing countries. The aim of this study is to compare pharmacokinetics profile of a new Imatinib generic formulation (Imatinib tablets 400mg batch number: 2090602, Hikma Pharmaceuticals PLC) with those of Glivec, (batch number: S0143, Novartis Pharma AG, Basle, Switzerland) in healthy male volunteers /fed state. The study was single center, randomized, single dose, laboratory-blinded, 2-period, 2-sequence, crossover design. The study was performed by CRO Algorithme Pharma Inc, (Quebec, Canada) in accordance with Good Clinical Practices and the applicable regulatory requirements. Male volunteers, non- or ex-smokers, of at least 18 years of age but not older than 55 years with a body mass index (BMI) greater than or equal to 18.5 and below 30 kg/m2 were selected according to the inclusion and exclusion criteria. In each study period, a single 400 mg dose of Imatinib was orally administered with about 240 mL of water in the morning after a 10-hour overnight fast, thirty (30) minutes after the start of a high-fat, high-calorie breakfast. Subjects remained seated for at least the first 4 hours following each drug administration. In each study period, twenty (20) blood samples were collected by venipuncture in pre-cooled Vacutainers containing EDTA. The first blood sample (2 x 4 mL) was collected prior to drug administration while the others (1 x 4 mL each) were collected at 1, 1.5, 2, 2.33, 2.67, 3, 3.33, 3.67, 4, 4.5, 5, 6, 8, 10, 14, 18, 24, 48 and 72 hours post drug administration. The drug administrations were separated by at least 14 calendar days. Urine drug and ethyl alcohol screening was performed before each period of the study. Hematology and biochemistry tests were repeated after the collection of the last blood sample of the study. Safety was evaluated through the assessment of adverse events, and laboratory tests. Imatinib plasma samples were analyzed employing a validated HPLC method using MS/MS detection. For a 400 mg dose of Imatinib, the analytical range was approximately 10 ng/mL to 4000 ng/mL. Descriptive statistics were used to summarize adverse events, safety results and demographic variables (age, height, weight and BMI). The main pharmacokinetic parameters of interest for this study were Cmax, AUC0-T and AUC0-8. Other parameters such as Tmax, AUCT/8, Kel and T1/2el were provided for information purposes only. The natural logarithmic transformation of Cmax, AUC0-T and AUC0-8 was used for all statistical inference. The mean (C.V. %) of Cmax, Tmax, AUC0-T and AUC0-8 (for Imatinib were 1760.5 ng/ml (26.6%), 3.67 hrs (26.4%), 30946.5 ng.h/ml (28.0%) and 31912.5 ng.h/ml (28.2%) versus 1779.4 ng/ ml (25.8%), 3.67 hrs (39.0%), 31073.6 ng.h/ml (25.7%) and 32270.9 ng.h/ml (26.4%) for Glivec. The 90% confidence intervals of Cmax, AUC0-T and AUC0-8 for Imatinib 400 mg were (92.00%-105.52%), (95.69%-102.31%) and (95.23%- 101.55%) respectively. The ratio of the geometric LS means for the test to reference Cmax , AUC0-T and AUC0-8 for Imatinib 400 mg were 98%, 99% and 99% respectively with low ISCV 12.9 % for Cmax and 6.3 % for AUC0-T and 6.0% for AUC0-8. The results indicated that the products are equivalent and switchable according to FDA rulings....
The purpose of this study was to evaluate bioequivalence of a combine formulation of pioglitazone/metformin 15/850 mg tablet with those of an established branded formulation. An open-label, single-dose, randomized, 2-way crossover study was conducted in fasted healthy Pakistani male volunteers. The concentrations of pioglitazone and metformin in plasma were analyzed by reverse phase High Performance Liquid Chromatography (HPLC). The plasma concentration-time curves were used to obtain pharmacokinetic parameters including AUC0-t, AUC0-8, and Cmax. The formulations were considered bioequivalent if the 90% confidence intervals (CIs) for AUC, and Cmax fell within the interval of 80% to 125%, declared in bioequivalence guidelines. On analysis of variance, no period, formulation or sequence effects were observed for any pharmacokinetic property. The 90% confidence intervals of pioglitazone for the geometric mean ratios of Cmax, AUC0-t and AUC0-8 were 93.34% to 103.12%, 86.15% to 106.03% and 85.62% to 107.41%, respectively. Similarly, the 90% CIs of metformin for the geometric mean ratios of Cmax, AUC0-t and AUC0-8 were 87.64% to 100.85%, 86.68% to 116.15 and 94.14% to 122.71%, respectively, qualifying the predetermined criteria for bioequivalence based on the rate and extent of absorption....
Quetiapine is an atypical antipsychotic indicated for the treatment of schizophrenia and related psychoses. Uses of generic drugs are essential due to economic reason. Interchangeability of drugs is determined by bioequivalence studies. We aim to study the bioequivalence of a generic quetiapine (Ketipinor�®, Orion Corporation, Finland) and the innovator product (Seroquel�®, AstraZeneca, UK). The study was a randomized, two-way crossover design with a two-week washout period in 24 healthy Thai male volunteers. After a single 200-mg oral dosing, serial blood samples were collected at appropriate interval up to 48 h. Plasma quetiapine concentrations were determined by using a validated LC-MS/MS method. Pharmacokinetic parameters were estimated using the WinNonlin�® software with noncompartment model analysis. The mean �± SD of maximum plasma concentration (Cmax), the area under the plasma concentration-time curve from 0 to 48 h (AUC0-last) and the area under the plasma concentration-time curve from 0 to infinity (AUC0-8) of Ketipinor�® v.s. Seroquel�® were 632.27 �± 304.43 v.s. 638.83 �± 214.49 ng/ml; 2,625.21 �± 972.14 v.s. 2,511.82 �± 704.21 ng.h/ml and 2,640.25 �± 979.10 v.s. 2,526.45 �± 704.37 ng.h/ml, respectively. The time to reach Cmax (Tmax) of Ketipinor�® and Seroquel�® were 1.34 �± 1.11 and 1.01 �± 0.63 h., respectively. The Tmax of Ketipinor�® was within the acceptance range of �±20% of the median Tmax of the reference product. The 90% confidence interval of the ratios of the log-transformed data of Cmax, AUC0-last and AUC0-8 were 80.75 - 102.60%, 91.32 - 108.42% and 88.47 - 106.77%, respectively, which were within the acceptance range of 80.00 - 125.00%. Power of the test for Cmax, AUC0-last and AUC0-8 were 92.16%, 96.34% and 95.96%, respectively. In conclusion, Ketipinor�® was bioequivalent to Seroquel�® in terms of both the rate and extent of absorption under fasting condition....
Objective: The purpose of this study was to compare the bioequivalence of 10 mg tablets of olanzapine between a generic drug (Olapin�®-10; Unison Laboratories Co., Ltd., Thailand) and a reference drug (Zyprexa�®,Eli Lilly, England) in healthy volunteers. Subjects and methods: A single dose, randomized, 2-period, 2-sequence, crossover study was conducted in 24 healthy Thai male and female volunteers. Each volunteer received a 10 mg tablet of the reference or test drug under fasting condition with a washout period of at least 21 days. Blood samples were obtained at pre-dose and at various time points up to 120 hours after dosing. Olanzapine plasma concentrations were quantified by a validated method employing liquid chromatography with tandem mass spectrometry (LC-MS/MS). Results: 24 volunteers completed both treatment periods. The geometric mean ratios (GMR) (test/reference) between the two formulations of olanzapine were 95.76% (90%CI, 88.55-103.55%) for Cmax; 103.77% (97.49- 110.46%) for AUC0-120; and 104.39% (98.20-110.98%) for AUC0-8(obs). There was no statistical difference of the Tmax between the two formulations (p>0.05). One hundred and eight adverse events were reported from both formulations. Most of the adverse events were judged to be mild in intensity and did not require additional medical treatment. Conclusion: No significant difference in the analysed pharmacokinetic parameters was found between the two formulations of 10 mg olanzapine in the healthy Thai volunteers. The 90%CI of GMR of the pharmacokinetic parameters was entirely within the equivalence criteria (80-125%). Therefore, it can be concluded that this two olanzapine tablet formulations were considered bioequivalent....
Patents for Chinese herbal medicines can be difficult to obtain. When the active ingredients of an herbal formula are known, danfang (single herb prescriptions) is better protected with quantified composition claims. When the active ingredients are unknown, 'product by processing', 'method of processing', 'method of administration' and 'new use claims' are often powerful tools to distinguish a traditional danfang from 'the prior art'. Additional patents may also be filed continuously in the product development process. Existing patents for fufang (composite prescriptions) are primarily drafted to protect traditional herbal formulations. More efforts are needed to protect various herbal combinations and their multiple applications....
Background\nOne of the most critical problems about antimicrobial therapy is the increasing resistance to antibiotics. Previous studies have shown that there is a direct relation between erroneous prescription, dosage, route, duration of the therapy and the antibiotics resistance. Other important point is the uncertainty about the quality of the prescribed medicines. Some physicians believe that generic drugs are not as effective as innovator ones, so it is very important to have evidence that shows that all commercialized drugs are suitable for therapeutic use.\nMethods\nMicrobial assays were used to establish the potency, the Minimal Inhibitory Concentrations (MICs), the Minimal Bactericidal Concentration (MBCs), the critical concentrations, and the production of spontaneous mutants that are resistant to vancomycin.\nResults\nThe microbial assay was validated in order to determine the Vancomycin potency of the tasted samples. All the products showed that have potency values between 90 - 115% (USP requirement). The products behave similarly because the MICs, The MBCs, the critical concentrations, the critical concentrations ratios between standard and samples, and the production of spontaneous mutants don't have significant differences.\nConclusions\nAll products analyzed by microbiological tests, show that both trademarks and generics do not have statistical variability and the answer of antimicrobial activity Show also that they are pharmaceutical equivalents....
Background\nDrug regulatory agencies (DRA) support prescription of generic products of intravenous antibiotics assuming therapeutic equivalence from pharmaceutical equivalence. Recent reports of deaths associated with generic heparin and metoprolol have raised concerns about the efficacy and safety of DRA-approved drugs.\nMethodology/Principal Findings\nTo challenge the assumption that pharmaceutical equivalence predicts therapeutic equivalence, we determined in vitro and in vivo the efficacy of the innovator product and 20 pharmaceutically equivalent generics of gentamicin. The data showed that, while only 1 generic product failed in vitro (MIC = 45.3 vs. 0.7 mg/L, P<0.05), 10 products (including gentamicin reference powder) failed in vivo against E. coli due to significantly inferior efficacy (Emax = 4.81 to 5.32 vs. 5.99 log10 CFU/g, P=0.043). Although the design lacked power to detect differences in survival after thigh infection with P. aeruginosa, dissemination to vital organs was significantly higher in animals treated with generic gentamicin despite 4 days of maximally effective treatment.\nConclusion\nPharmaceutical equivalence does not predict therapeutic equivalence of generic gentamicin. Stricter criteria based on solid experimental evidence should be required before approval for human use....
The aim of this study is to assess the quality of Valzan(�®) tablet (160 mg, valsartan immediate release test formulation) by comparing its pharmacokinetic parameters with Diovan(�®) tablet (160 mg, valsartan reference formulation). Valzan(�®) tablets were prepared according to a dry granulation method (roll compaction). To assess the bioequivalence of Valzan(�®) tablets a randomized, two-way, crossover, bioequivalence study was performed in 24 healthy male volunteers. The selected volunteers were divided into two groups of 12 subjects. One group was treated with the reference formulation (Diovan(�®)) and the other one with the generic Valzan(�®), with a cross-over after the drug washout period of 14 days. Blood samples were collected at fixed time intervals and valsartan concentrations were determined by a validated HPLC assay method. The pharmacokinetic parameters AUC(0-48), AUC(0-8), C(max), T(max), K(e) and T(1/2) were determined for both the tablets and were compared statistically to evaluate the bioequivalence between the two brands of valsartan, using the statistical model recommended by the FDA. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals (CI) fell within the acceptable range for bioequivalence. Based on this statistical evaluation it was concluded that the test tablets (Valzan(�®)) is well formulated, since it exhibits pharmacokinetic profile comparable to the reference brand Diovan(�®)....
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