scholarly journals lanning and Evaluation of Bioequivalence Studies of Telmisartan Generic Drug Products

2019 ◽  
Vol 8 (3) ◽  
pp. 101-106
Author(s):  
A. L. Khokhlov ◽  
D. P. Romodanovsky ◽  
A. E. Miroshnikov
Keyword(s):  
Confidence Interval ◽  
Generic Drug ◽  
Generic Drugs ◽  
Intraindividual Variability ◽  
Pharmacokinetic Parameters ◽  
Key Factors ◽  
Limit Of Quantification ◽  
Optimal Method ◽  
Reference Drug ◽  
Upper Limit

Introduction. Telmisartan is a modern antihypertensive drug, from the group of angiotensin II receptor antagonists, which, recently, has been the purpose of the development and registration of generic drug. The pharmaceutical development of telmisartan generics and their evaluation in bioequivalence studies is complicated by many factors that influence the results of comparison with the reference drug. Therefore, it is relevant to study these factors for the proper planning of studies and for evaluating their results from the generic drugs of telmisartan.Aim. The aim of the study is to identify the key factors that should be considered in planning and evaluation of bioequivalence studies of telmisartan’s generics.Materials and methods. To identify the key factors influencing the planning and evaluation of studies of telmisartan generics, a retrospective analysis of the results of seven telmisartan studies was conducted. Calculated pharmacokinetic parameters Cmax, AUC0-t, tmax; their average values; the values of intraindividual variability for each study and the average of the coefficients of intraindividual variability obtained.Results and discussion. The results of the study demonstrated that the drugs of telmisartan are highly variable, there are sex differences in the pharmacokinetics of telmisartan. According to the averaged values of the concentrations and pharmacokinetic profiles of telmisartan, the following areas were determined: the area of maximum exposure of telmisartan, the duration and schedule of blood sampling, to obtain the optimal pharmacokinetic profile. The most optimal method for the determination of telmisartan is HPLC MS/MS with a lower limit of quantification in the range of 0.5–3 ng/ml. The upper limit of the 90% confidence interval was calculated for the pooled average of the coefficients of intraindividual variability obtained in the considered studies.Conclusion. Recommendations were developed for planning and evaluating bioequivalence studies of generic telmisartan preparations. It is necessary to plan bioequivalence studies with replicated design in three or four periods, with two crossovers, with two sequences of drug intake. To assess the pharmacokinetics of telmisartan one should use the data on its exposure given in the article. When determining the sample size, one should be guided by the upper limit of the confidence interval of the averaged values of the coefficient of intra-individual variability Cmax of telmisartan (45%). Evaluation of results should be carried out taking into account the possibility of scaling bioequivalence limits for the Cmax. The bioequivalence limit for the AUC0-t parameter should remain in the range of 80.00–125.00%, as well as the ratio of geometric means for both parameters.

scholarly journals Review of bioequivalence studies of cholecalciferol drugs

2020 ◽  
Vol 6 (3) ◽  
pp. 21-26
Author(s):  
Alexander L. Khokhlov ◽  
Dmitry P. Romodanovsky
Keyword(s):  
Systematic Review ◽  
Gender Differences ◽  
Comparative Analysis ◽  
Retrospective Analysis ◽  
Healthy Adult ◽  
Generic Drugs ◽  
Intraindividual Variability ◽  
Pharmacokinetic Parameters ◽  
Reference Drug ◽  
Endogenous Compounds

Introduction: The general requirements for assessing bioequivalence of endogenous drugs are described in the relevant guidelines, but they do not provide a complete picture of how to adequately develop a design of such a study. The aim of this article is to offer recommendations on the development of a design for bioequivalence studies of endogenous drugs, using cholecalciferol as an example. Materials and methods: A systematic review of our database on the results of bioequivalence studies of generic drugs revealed one study of cholecalciferol drugs, which was performed using a simple cross-over design. The study involved 24 healthy adult subjects. The data of 24 volunteers were retrospectively analyzed to identify endogenous cholecalciferol concentrations and intraindividual variability (CVintra) for Cmax and AUC0-t. As part of a retrospective analysis, we also assessed gender differences of pharmacokinetics. Results and discussion: Assessment of the bioequivalence of cholecalciferol drugs was complicated by the presence of endogenous concentrations of cholecalciferol for the tested drug – 1.27 (±0.55) ng/ml and for the reference drug – 0.98 (±0.55) ng/ml. The results of the analysis of the intraindividual variability of Cmax and AUC0-72 of the tested and reference drugs showed the following CVintra values – 22.80% and 21.58%, respectively. A comparative analysis of pharmacokinetic parameters did not reveal statistically significant gender differences. The article presents approaches to the planning of future bioequivalence studies of cholecalciferol drugs. Conclusion: Cholecalciferol is not a highly variable drug; however, it relates to drugs – analogues of endogenous compounds, which requires determining the endogenous concentrations.

scholarly journals COMPARISON BETWEEN GENERIC DRUGS AND BRAND NAME DRUGS FROM BIOEQUIVALENCE AND THERMOEQUIVALENCE PROSPECTIVE

2017 ◽  
Vol 9 (6) ◽  
pp. 1 ◽  
Author(s):  
Mosab Arafat ◽  
Zahaa Ahmed ◽  
Osama Arafat
Keyword(s):  
Generic Drug ◽  
Active Ingredient ◽  
Generic Drugs ◽  
Pharmacokinetic Parameters ◽  
Drug Preparation ◽  
Brand Name ◽  
Drug Bioavailability ◽  
Polymer Carrier ◽  
Inactive Ingredients ◽  
Brand Name Drugs

The belief that generic drugs are inferior to brand name drugs has been always under debate. Especially since the price of generic drugs is generally far cheaper than brand-name drugs. Although, this is because of waiving the preclinical studies and clinical trials for the generic drug, the quality, and purity of materials used for generic drug preparation is still arguable. Thus, the objective of this overview was to find out the tolerable deviations between generic and brand name drugs which should not alter the pharmacology. Using inactive additives in the generic drug different than in the brand name drug, such as binders, glidants, diluents, anti-adherents, disintegrants or polymer carrier material and filler should not change the drug bioavailability and pharmacokinetic parameters as long as both products using the identical active ingredient(s) in equivalent amounts. Even if both drug products are bioequivalent to each other in terms of active ingredient, they are not in terms of inactive ingredients. Hence, the probability of unexpected adverse drug reaction and allergies from the generic formulation are possible, especially, when people react sensitive toward specific component. Therefore, the occasional negative response occurring upon the switch from brand-name drug to the generic drug can be attributed to intra-and inter-patient variations toward inactive ingredients. Variations toward inactive ingredients can be obtained experimentally by utilizing a proper thermoanalytical technique. As a result, thermoequivalence of generic drugs to brand name drugs can be determined based on thermal information obtained from both products. In conclusion, thermoequivalence study can be a useful tool to demonstrate any possible variation between the inactive ingredients of both products.

scholarly journals Lixarit — clinical and pharmaceutical aspects of efficacy and safety of flecainide acetate generic drug

HYPERTENSION ◽  
2021 ◽  
Vol 14 (4) ◽  
pp. 21-25
Author(s):  
N.V. Bezditko
Keyword(s):  
Health Care ◽  
Generic Drug ◽  
Antiarrhythmic Agent ◽  
Efficacy And Safety ◽  
Reference Drug ◽  
Flecainide Acetate

The article considers the use of flecainide, an antiarrhythmic agent. The results of comparing the bioequivalence of Lixarit, flecainide acetate generic drug (flecainide acetate, 100 mg tablets, Laboratorios Normon SA, Spain), and Apocard®, flecainide acetate reference drug (Health Care Ltd, UK, 100 mg tablets), are presented.

scholarly journals Relative toxicity of benzodiazepines and hypnotics commonly used for self-poisoning: An epidemiological study of fatal toxicity and case fatality

2018 ◽  
Vol 32 (6) ◽  
pp. 654-662 ◽  
Author(s):  
Galit Geulayov ◽  
Anne Ferrey ◽  
Deborah Casey ◽  
Claudia Wells ◽  
Alice Fuller ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Case Fatality ◽  
Practice Research ◽  
Clinical Practice Research Datalink ◽  
Relative Toxicity ◽  
Reference Drug ◽  
Alcohol Involvement ◽  
Self Harm ◽  
Hypnotic Drugs ◽  
Using Data

The relative toxicity of anxiolytic and hypnotic drugs commonly used for self-poisoning was assessed using data on suicides, prescriptions and non-fatal self-poisonings in England, 2005–2012. Data on suicide by self-poisoning were obtained from the Office for National Statistics, information on intentional non-fatal self-poisoning was derived from the Multicentre Study of Self-harm in England and data on prescriptions in general practice from the Clinical Practice Research Datalink. We used two indices of relative toxicity: fatal toxicity (the number of fatal self-poisonings relative to the number of individuals prescribed each drug) and case fatality (the number of fatal relative to non-fatal self-poisonings). Diazepam was the reference drug in all analyses. Temazepam was 10 times (95% confidence interval 5.48–18.99) and zopiclone/zolpidem nine times (95% confidence interval 5.01–16.65) more toxic in overdose than diazepam (fatal-toxicity index). Temazepam and zopiclone/zolpidem were 13 (95% confidence interval 6.97–24.41) and 12 (95% confidence interval 6.62–22.17) times more toxic than diazepam, respectively (case-fatality index). Differences in alcohol involvement between the drugs were unlikely to account for the findings. Overdoses of temazepam and zopiclone/zolpidem are considerably more likely to result in death than overdoses of diazepam. Practitioners need to exercise caution when prescribing these drugs, especially for individuals who may be at risk of self-harm, and also consider non-pharmacological options.

Pharmacokinetics and bioequivalence of generic etoricoxib in healthy volunteers

2021 ◽  
Vol 10 (3) ◽  
pp. 113-118
Author(s):  
Nishalini Harikrishnan ◽  
Ka-Liong Tan ◽  
Kar Ming Yee ◽  
Alia Shaari Ahmad Shukri ◽  
Nalla Ramana Reddy ◽  
...  
Keyword(s):  
Compartmental Analysis ◽  
Bioequivalence Study ◽  
Active Pharmaceutical Ingredient ◽  
Pharmacokinetic Profile ◽  
Time Profile ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Reference Drug ◽  
Test Formulation ◽  
R Ratio

Introduction/Study Objectives: A bioequivalence study was performed to compare the pharmacological profile of innovator etoricoxib (ETO) with a newly developed generic ETO, both in a 120 mg tablet formulation. A dissolution study was conducted to optimize the formulation process before evaluating physical changes in the active pharmaceutical ingredient and the formulated product. Methods: This was a randomized, open-label, balanced, two-treatment, two-period, two-sequence, single-dose, two-way crossover, truncated bioequivalence study involving a washout period of ten days. A total of 26 healthy male volunteers were recruited. The pharmacokinetic profile of the test formulation was compared with the reference formulation. Results/Discussion: The pharmacokinetic parameters of ETO were calculated based on the plasma drug concentration-time profile using non-compartmental analysis to determine its safety profile and tolerability. The Test/Reference (T/R) ratio of ETO was 104.36% (90% confidence interval (CI): 98.30%–110.80%) for area under curve (AUC)0-72 while the T/R ratio of maximum concentration (Cmax) was 101.39% (92.15%–111.56%). The 90% CI of the Cmax and AUC0-72 of ETO were within acceptable bioequivalence limits of 80%–125%. All values were within the predetermined limits of the Association of Southeast Asian Nation (ASEAN) bioequivalence guidelines. Conclusion: The test formulation was found to be bioequivalent with respect to the reference drug, according to ASEAN bioequivalence guidelines.

scholarly journals Assessment of in Vitro Comparative Dissolution Kinetics of Moxonidine Products as a Factor Potentially Determining Effectiveness of Antihypertensive Treatment

2019 ◽  
Vol 14 (6) ◽  
pp. 951-957
Author(s):  
G. V. Ramenskaya ◽  
I. E. Shokhin ◽  
N. I. Gaponova ◽  
V. R. Abdrakhmanov
Keyword(s):  
Generic Drugs ◽  
Dissolution Kinetics ◽  
Acetate Buffer Solution ◽  
Medicinal Products ◽  
Buffer Solution ◽  
Reference Drug ◽  
Similarity Factor ◽  
Kinetics Of ◽  
Comparative Dissolution

Aim. Investigation of comparative dissolution kinetics of generic medicinal products containing moxonidine versus reference drug. Material and methods. Objects of the research were film-coated tablets containing moxonidine (INN) in a dose 0.4 mg: a reference drug Physiotens® and 4 generic drugs. In vitro dissolution test of moxonidine from the study drugs was performed using comparative dissolution kinetics test (CDKT). The CDKT was performed in the media with the following pH: 1.2 (1:9 mixture of 0.1 M hydrochloric acid and water), 4.5 (acetate buffer solution, prepared as per State Pharmacopoeia, XIII), and 6.8 (phosphate buffer solution, prepared as per State Pharmacopoeia, XIII). The sampling for dissolved moxonidine was performed 5, 10, 15, 20, and 30 min after the test was started. An high performance liquid chromatography method with ultraviolet detection at 220 nm was used to assay. Results. Within 15 min more that 85% of moxonidine dissolved from the reference drug and all study drugs at pH 1.2; dissolution profiles were similar without calculation of similarity factor f2. Similarly, at pH 4.5 dissolution profiles of study drugs #2 and #3 were similar to that of the reference drug, and the similarity factor f2 was not calculated. However, in case of study drugs #1 and #4 significant differences were observed at a single time point (15 min), which suggests that their dissolution profiles are non-similar to that of the reference drug. Similarity factors f2 were calculated 17.52 and 35.30, respectively (less than 50). At pH 6.8 similarity factors f2 for all study generic drugs were also less than 50 (23.8, 49.8, 38.6, and 35.9), so their dissolution curves were non-similar to that of reference drug. Conclusion. In our study we observed difference in release in vitro of medicinal products containing moxonidines: none of the study drugs was fully similar to the reference drug in all media. The differences observed at pH 6.8 were noteworthy, where the samples had or faster kinetics (study drugs #2 and #3), or slower dissolution kinetics (test drugs #1 and #4). Observed differences in moxonidine release rate may impact absorption of active pharmaceutical ingredient into the blood following drug administration.

scholarly journals Pharmacokinetics and Bioequivalence of Rasagiline Tablets in Chinese Healthy Subjects Under Fasting and Fed Conditions: An Open, Randomized, Single-Dose, Double-Cycle, Two-Sequence, Crossover Trial

2020 ◽  
Vol 11 ◽  
Author(s):  
Yinjuan Li ◽  
Lu Qi ◽  
Haihong Bai ◽  
Ying Liu ◽  
Rongxia Fan ◽  
...  
Keyword(s):  
Single Dose ◽  
Healthy Subjects ◽  
Geometric Mean ◽  
Pharmacokinetic Parameters ◽  
Serious Adverse Events ◽  
Good Tolerability ◽  
Clinical Trial Registration ◽  
Reference Drug ◽  
Healthy Chinese ◽  
Chinese Subjects

Objective: This study evaluated the pharmacokinetics, safety, and bioequivalence (BE) of two formulations of rasagiline tablets in healthy Chinese subjects under fasting and fed conditions.Methods: An open, randomized, single-dose, double-cycle, two-sequence, self-crossover pharmacokinetic study in healthy Chinese subjects under fasting and high-fat postprandial conditions was performed. A total of 108 healthy subjects (36 in the fasting group and 72 in the postprandial group) were recruited. In each cycle of the study under both conditions, subjects received a single oral dose of 1 mg of a test or reference preparation of rasagiline tablets (1 mg each). A washout period of 3 days was observed. Blood samples were obtained up to 10 h post-intake. Primary endpoints were the BE of major pharmacokinetic parameters (AUC0–t and AUC0–∞) and the maximum observed serum concentration (Cmax). Secondary endpoints were safety parameters.Results: The 90% confidence interval (CI) of the geometric mean ratio (GMR) of the test drug vs. the reference drug for rasagiline was 94.16–105.35% for the AUC0–t under fasting conditions and 99.88–107.07% under postprandial conditions. The 90% CIs for the AUC0–∞ were 93.55–105.01% and 99.59–107.05% under fasting and postprandial conditions, respectively. The 90% CIs for the Cmax were 88.26–108.46% and 89.54–118.23% under fasting and postprandial conditions, respectively. The 90% CIs for the test/reference AUC ratio and Cmax ratio were within the acceptable range (0.80–1.25) for BE. In this BE study, there were no serious adverse events (AEs).Conclusion: BE between the test and the reference products was established in both fasting and postprandial conditions. The two formulations of rasagiline showed good tolerability and a similar safety profile.Clinical Trial Registration:chinaDrugtrials.org.cn, identifier CTR20181466.

Therapeutic Equivalence and the Generic Competition Paradox

2012 ◽  
Vol 12 (1) ◽  
Author(s):  
Munirul Haque Nabin ◽  
Vijay Mohan ◽  
Aaron Nicholas ◽  
Pasquale M. Sgro
Keyword(s):  
Simple Model ◽  
Generic Drug ◽  
Generic Drugs ◽  
Large Body ◽  
Medical Community ◽  
Therapeutic Equivalence ◽  
Generic Competition ◽  
Branded Drug ◽  
Fda Approval ◽  
Generic Products

Abstract Following the passage of the Waxman-Hatch Act (1984), FDA approval for a generic drug requires the establishment of bio-equivalence between the generic drug and an FDA approved branded drug. However, a large body of evidence in the medical community suggests that bio-equivalence does not guarantee therapeutic equivalence; in some instances the lack of therapeutic equivalence can lead to fatal consequences for patients switching to generic products. In this paper, we construct a simple model to analyze the implications of therapeutic non-equivalence between branded and generic drugs. We show, theoretically and empirically, that this distinction can provide a plausible explanation of the generic competition paradox.

Generic Drugs—A Look Back and a Look Ahead

1990 ◽  
Vol 3 (3) ◽  
pp. 192-202
Author(s):  
Leon Lachman ◽  
Salvatore Turco ◽  
James T. O'Donnell
Keyword(s):  
Generic Drug ◽  
Generic Drugs ◽  
Drug Industry ◽  
Look Ahead ◽  
Look Back

This review includes the viewpoints of three pharmaceutical scientists tracing the origins of the generic drug industry, examining the recent generic drug controversies, and offering suggestions to hospital practitioners for coping with the controversies.

scholarly journals 1552. Correlation Between Vancomycin Serum Trough Concentrations and Area Under the Curve in Pediatric Patients

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S566-S567
Author(s):  
Krista Weaver ◽  
Madan Kumar ◽  
Allison Nelson ◽  
Palak Bhagat
Keyword(s):  
Pediatric Patients ◽  
Retrospective Chart Review ◽  
Primary Study ◽  
Pharmacokinetic Parameters ◽  
Optimal Method ◽  
Study Objective ◽  
Serum Trough ◽  
Trough Concentrations ◽  
Group 2 ◽  
Group 1

Abstract Background Despite years of experience with vancomycin (VAN), the optimal method to monitor VAN therapy in pediatric patients is still unknown. Recent pediatric data indicate serum trough concentrations lower than 10–20 mg/L or 15–20 mg/L based on indication may achieve an AUC24> 400 mg hours/L. The primary study objective was to compare AUC24 to goal VAN serum trough concentrations (STC). Methods A retrospective chart review of pediatric patients who received intravenous VAN June 1, 2018 to December 31, 2018 was completed. AUC24 was calculated using a trapezoidal method with 2 steady-state serum concentrations. A serum peak concentration was drawn 1 hour and 15 minutes following the end of infusion and an STC was drawn 30 minutes prior to infusion. Results During 25 admissions, 12 patients had a first AUC24 at goal and 13 patients had a first AUC24 below goal. Of 41 AUC24 calculations, 27 AUC24s were ≥400 mg hours/L (group 1), and 14 AUC24s were <400 mg hours/L (group 2). Median AUC24 was 561 mg hours/L for group 1 vs. 344.5 mg hours/L for group 2 (P < 0.001). Correlating Cmin and Ctrough (Ctr) for group 1 and group 2 were 12 mg/L and 13.5 mg/L vs. 6.4 mg/L and 7.3 mg/L, respectively (P < 0.001). Figure 1 shows the pharmacokinetic parameters for each group. Spearman correlation between AUC24 and Cmin was 0.87. Of the 35 subtherapeutic VAN STCs, 20 (57.1%) achieved an AUC24 ≥400 mg hours/L (P = 0.08). Subgroup analysis of AUC24 400–600 mg hours/L showed a median AUC24 of 519 mg hours/L with correlating Cmin and Ctr of 10.6 mg/L and 11.9 mg/L, respectively. The MIC was <1 in 90.9% of cases (Figure 2). The mean VAN dose required to achieve an AUC24 ≥400 mg hours/L was 77.7 mg/kg/day; dosing frequency did not appear to affect AUC24 outcome. Time to culture clearance was 2 days in group 1 and 6.5 days in group 2 (P = 0.24). No cases of nephrotoxicity were identified despite AUC24 values ranging from 265–1294 mg hours/L. Conclusion AUC24 monitoring using a 2-sample trapezoidal method was successfully implemented at this institution. The results of this study align with previous pediatric studies, supporting the use of lower serum trough concentration goals of 10–15 mg/L. Disclosures All authors: No reported disclosures.

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