Context: The assessment absolute bioavailability of oral hydrocortisone is complicated by its saturable binding to cortisol binding globulin (CBG). Previous assessment of bioavailability used a cortisol radioimmunoassay which has cross reactivity with other steroids. Salivary cortisone is a measure of free cortisol and LC-MS/MS is the gold standard method for measuring steroids. We here report the absolute bioavailability of hydrocortisone calculated using serum cortisol and salivary cortisone measured by LC-MS/MS.
Methods: 14 healthy male dexamethasone suppressed volunteers were administered 20 mg hydrocortisone either intravenously or orally by tablet. Samples of serum and saliva were taken and measured for cortisol and cortisone by LC-MS/MS. Serum cortisol was corrected for saturable binding using published data and pharmacokinetic parameters derived using the program WinNonlin.
Results: The mean (95% CI) bioavailability of oral hydrocortisone calculated from serum cortisol, unbound serum cortisol and salivary cortisone was 1.00 (0.89-1.14); 0.88 (0.75-1.05); and 0.93 (0.83-1.05), respectively.
Conclusion: The data confirm that, after oral administration, hydrocortisone is completely absorbed. The data derived from serum cortisol corrected for protein binding, and that from salivary cortisone, are similar supporting the concept that salivary cortisone reflects serum free cortisol levels and that salivary cortisone can be used as a non-invasive method for measuring the pharmacokinetics of hydrocortisone.
{"title":"Bioavailability of Oral Hydrocortisone Corrected for Binding Proteins and Measured by LC-MS/MS Using Serum Cortisol and Salivary Cortisone.","authors":"T N Johnson, M J Whitaker, B Keevil, R J Ross","doi":"10.4172/jbb.1000365","DOIUrl":"https://doi.org/10.4172/jbb.1000365","url":null,"abstract":"<p><strong>Context: </strong>The assessment absolute bioavailability of oral hydrocortisone is complicated by its saturable binding to cortisol binding globulin (CBG). Previous assessment of bioavailability used a cortisol radioimmunoassay which has cross reactivity with other steroids. Salivary cortisone is a measure of free cortisol and LC-MS/MS is the gold standard method for measuring steroids. We here report the absolute bioavailability of hydrocortisone calculated using serum cortisol and salivary cortisone measured by LC-MS/MS.</p><p><strong>Methods: </strong>14 healthy male dexamethasone suppressed volunteers were administered 20 mg hydrocortisone either intravenously or orally by tablet. Samples of serum and saliva were taken and measured for cortisol and cortisone by LC-MS/MS. Serum cortisol was corrected for saturable binding using published data and pharmacokinetic parameters derived using the program WinNonlin.</p><p><strong>Results: </strong>The mean (95% CI) bioavailability of oral hydrocortisone calculated from serum cortisol, unbound serum cortisol and salivary cortisone was 1.00 (0.89-1.14); 0.88 (0.75-1.05); and 0.93 (0.83-1.05), respectively.</p><p><strong>Conclusion: </strong>The data confirm that, after oral administration, hydrocortisone is completely absorbed. The data derived from serum cortisol corrected for protein binding, and that from salivary cortisone, are similar supporting the concept that salivary cortisone reflects serum free cortisol levels and that salivary cortisone can be used as a non-invasive method for measuring the pharmacokinetics of hydrocortisone.</p>","PeriodicalId":15184,"journal":{"name":"Journal of Bioequivalence & Bioavailability","volume":"10 1","pages":"001-3"},"PeriodicalIF":0.0,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4172/jbb.1000365","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36127196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
During the past decades, the complexity of clinical trials has grown dramatically due to geographic dispersion, site related issues, treatment choices, standard of care and regulatory uncertainty. The uncertainty have created opportunity for the Risk Based Monitoring (RBM) / centralize monitoring due to use of electronic system, changes in statistical assessment, improvement in clinical trial documents. RBM has emerged as the future of clinical development. This approach is supported by the US-FDA, European Medicines Agency (EMA) and several other regulatory agencies. Fabrication of data, fraud, data distribution errors and other data anomalies that can be readily found by risk-based monitoring policies and procedures. RBM improves quality and efficiency of sponsor to oversight clinical sites and help to save significant cost. It helps to quickly identify signals that could affect quality and operational performance. It is concluded that, efficient planning lays the foundation of an effective risk-based monitoring strategy.
{"title":"Impacts and Implications of Risk Based Monitoring: A CRO Perspective","authors":"Prashant A Pandya","doi":"10.4172/jbb.10000e83","DOIUrl":"https://doi.org/10.4172/jbb.10000e83","url":null,"abstract":"During the past decades, the complexity of clinical trials has grown dramatically due to geographic dispersion, site related issues, treatment choices, standard of care and regulatory uncertainty. The uncertainty have created opportunity for the Risk Based Monitoring (RBM) / centralize monitoring due to use of electronic system, changes in statistical assessment, improvement in clinical trial documents. RBM has emerged as the future of clinical development. This approach is supported by the US-FDA, European Medicines Agency (EMA) and several other regulatory agencies. Fabrication of data, fraud, data distribution errors and other data anomalies that can be readily found by risk-based monitoring policies and procedures. RBM improves quality and efficiency of sponsor to oversight clinical sites and help to save significant cost. It helps to quickly identify signals that could affect quality and operational performance. It is concluded that, efficient planning lays the foundation of an effective risk-based monitoring strategy.","PeriodicalId":15184,"journal":{"name":"Journal of Bioequivalence & Bioavailability","volume":"43 1","pages":"1-2"},"PeriodicalIF":0.0,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74223386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-01-01DOI: 10.4172/0975-0851.1000371
P. Baumann
Pharmacotherapy in psychiatry is characterised by a clinical response of patients frequently delayed by several days or even weeks. Moreover, there are no firm biological parameters which can be monitored to get an objective picture of the clinical outcome in patients suffering from schizophrenia or an affective disorder, except for some adverse effects. Therapeutic drug effects are often subtle, changes in psychopathology have to be measured using adequate rating scales. Such scales are also used for the qualitative and quantitative analysis of adverse effects such as sedation, inner tension, anxiety, suicidal ideas, extrapyramidal symptoms. On the other hand, laboratory exams have to be included to monitor possible adverse effects at e.g. the haematological level [1,2]. Besides, patients often lack adherence to the treatment. This situation but also environmental, personal and genetic factors are responsible for a high interindividual variability of the metabolism and pharmacokinetics in the subjects. This variability has consequences on the pharmacodynamics of the therapeutic agents. Therefore, therapeutic drug monitoring and pharmacogenetics tests have been introduced as valid instruments to optimise treatment [3].
{"title":"Implementation of Therapeutic Drug Monitoring and Pharmacogenetic Tests in Psychiatry: How About ABCB1?","authors":"P. Baumann","doi":"10.4172/0975-0851.1000371","DOIUrl":"https://doi.org/10.4172/0975-0851.1000371","url":null,"abstract":"Pharmacotherapy in psychiatry is characterised by a clinical response of patients frequently delayed by several days or even weeks. Moreover, there are no firm biological parameters which can be monitored to get an objective picture of the clinical outcome in patients suffering from schizophrenia or an affective disorder, except for some adverse effects. Therapeutic drug effects are often subtle, changes in psychopathology have to be measured using adequate rating scales. Such scales are also used for the qualitative and quantitative analysis of adverse effects such as sedation, inner tension, anxiety, suicidal ideas, extrapyramidal symptoms. On the other hand, laboratory exams have to be included to monitor possible adverse effects at e.g. the haematological level [1,2]. Besides, patients often lack adherence to the treatment. This situation but also environmental, personal and genetic factors are responsible for a high interindividual variability of the metabolism and pharmacokinetics in the subjects. This variability has consequences on the pharmacodynamics of the therapeutic agents. Therefore, therapeutic drug monitoring and pharmacogenetics tests have been introduced as valid instruments to optimise treatment [3].","PeriodicalId":15184,"journal":{"name":"Journal of Bioequivalence & Bioavailability","volume":"16 1","pages":"22-23"},"PeriodicalIF":0.0,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84687186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In order to render the best possible outcome for effective in vivo human translatability of the preclinical efficacy measures for orally administered drugs certain clinical pharmacology attributes play a key role. In this regard, effective and predictable absorption is the most relevant one; followed by controlled and reasonable variability in the pharmacokinetic parameters. Hence oral bioavailability would be expected to play a vital role in delivering the drug to site(s) of action needed to attain the desired efficacy measures.
{"title":"Improved Oral Bioavailability and Variability Control in Pharmacokinetic Data – Role of Formulations","authors":"N. Srinivas","doi":"10.4172/jbb.10000e84","DOIUrl":"https://doi.org/10.4172/jbb.10000e84","url":null,"abstract":"In order to render the best possible outcome for effective in vivo human translatability of the preclinical efficacy measures for orally administered drugs certain clinical pharmacology attributes play a key role. In this regard, effective and predictable absorption is the most relevant one; followed by controlled and reasonable variability in the pharmacokinetic parameters. Hence oral bioavailability would be expected to play a vital role in delivering the drug to site(s) of action needed to attain the desired efficacy measures.","PeriodicalId":15184,"journal":{"name":"Journal of Bioequivalence & Bioavailability","volume":"33 1","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81875068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
L. Disch, K. Forsch, B. Siewert, J. Drewe, G. Fricker
Purpose: Aim of this study was to evaluate St. John’s wort (SJW) extract for its suitability to be formulated in a sustained release dosage form using Ze 117 as example extract. Methods: Hypericin as marker for naphtodianthrones and quercetin as marker for contained flavonoids in Ze 117 were evaluated for solubility through shake flask method and for in vitro permeability through Caco-2 monolayers. Furthermore, different intestinal segments were screened for absorption capacity of markers using an in situ rat model. Results: Over a physiological pH range, naphthodianthrones exhibited pH-dependent solubility profiles with best solubility at pH 6.8. In contrast, solubility of flavonoids was pH-independent. In Caco-2 monolayer system, low permeation was evident for naphthodianthrone hypericin, while the flavonoid quercetin showed high permeation. Results of in situ rat model showed absorption of hypericin and quercetin mainly in jejunum. Conclusion: SJW extract covers components with different physicochemical properties. Predominant absorption in rat intestinal segments indicated presence of an absorption window in small intestine. Furthermore, there is high drug concentration per single dose in combination with a complex extract mixture. Thus, development of a sustained release formulation for SJW extract is challenging.
{"title":"Sustained Release for St. John?s Wort: A Rational Idea?","authors":"L. Disch, K. Forsch, B. Siewert, J. Drewe, G. Fricker","doi":"10.4172/JBB.1000363","DOIUrl":"https://doi.org/10.4172/JBB.1000363","url":null,"abstract":"Purpose: Aim of this study was to evaluate St. John’s wort (SJW) extract for its suitability to be formulated in a sustained release dosage form using Ze 117 as example extract. \u0000Methods: Hypericin as marker for naphtodianthrones and quercetin as marker for contained flavonoids in Ze 117 were evaluated for solubility through shake flask method and for in vitro permeability through Caco-2 monolayers. Furthermore, different intestinal segments were screened for absorption capacity of markers using an in situ rat model. \u0000Results: Over a physiological pH range, naphthodianthrones exhibited pH-dependent solubility profiles with best solubility at pH 6.8. In contrast, solubility of flavonoids was pH-independent. In Caco-2 monolayer system, low permeation was evident for naphthodianthrone hypericin, while the flavonoid quercetin showed high permeation. Results of in situ rat model showed absorption of hypericin and quercetin mainly in jejunum. \u0000Conclusion: SJW extract covers components with different physicochemical properties. Predominant absorption in rat intestinal segments indicated presence of an absorption window in small intestine. Furthermore, there is high drug concentration per single dose in combination with a complex extract mixture. Thus, development of a sustained release formulation for SJW extract is challenging.","PeriodicalId":15184,"journal":{"name":"Journal of Bioequivalence & Bioavailability","volume":"5 1","pages":"565-576"},"PeriodicalIF":0.0,"publicationDate":"2017-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89101968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. A. González-Delgado, Padrón-Yaquis As, Daise Jiménez-Rodríguez, D. Cazanave-Guarnaluce, Alejo-Cisneros Pl, Tatiana Festary-Casanovas, M. Barrios-Sarmiento, Alina Díaz-Machado, Sonia Pérez-Rodríguez, Alis Martín-Trujillo, L. Barrero-Viera, I. García-García
Background: The implementation of generic drug development programs constitutes a basic component of the global health policy. The aim of this work is to determine the existence of bioequivalence between two prolonged release diclofenac sodium formulations in healthy volunteers. Methods: A phase I, randomized, crossover, double-blind clinical trial was conducted where pharmacokinetics in plasma and biological safety of Voltaren Retard® (reference formulation) and a generic prolonged-release Cuban diclofenac sodium formulation were compared. The sampling period was 24 hours, with a washout time of 15 days between each one. All subjects received, orally, a single dose of 100 mg (one tablet) of the corresponding formulation in each period. Results: Thirty-six volunteers, the half women, with a mean age of 33 years were included. White skin subjects were 56%. The quantification of diclofenac sodium in plasma by HPLC demonstrated a high similitude between formulations. The mean values of the pharmacokinetic parameters were: AUC24 (4924 vs. 4928 ng.h/mL), AUCinf (5046 vs. 5054 ng.h/mL), Cmax (1047 vs. 1042 μg/mL), t1/2 2.25 vs. 2.25 h), Median Tmax was 2 hours for both formulations. The preparations could be considered as bioequivalent according to ANOVA and 90% CI analysis. No formulation, period, sequential and residual effects were detected. The adverse events were mild, well tolerated, with a low frequency of onset. The most frequent events were hypertension, headache and increase in transaminases and urea values, registered in less than 10% of the subjects. Conclusion: Cuban prolonged-release diclofenac sodium formulation was bioequivalent with the commercial reference formulation Voltaren Retard®.
背景:仿制药开发项目的实施是全球卫生政策的一个基本组成部分。本研究的目的是确定两种缓释双氯芬酸钠制剂在健康志愿者体内的生物等效性。方法:采用随机、交叉、双盲I期临床试验，比较volaren Retard®(参比制剂)与古巴双氯芬酸钠缓释片仿制制剂的血浆药动学及生物安全性。采样周期为24小时，每次冲洗时间为15天。所有受试者在每个时期口服相应制剂的单剂量100mg(一片)。结果:36名志愿者，其中一半是女性，平均年龄为33岁。白皮肤受试者为56%。HPLC法测定血浆中双氯芬酸钠的含量具有高度的相似性。药动学参数的平均值分别为AUC24 (4924 vs 4928 ng.h/mL)、AUCinf (5046 vs 5054 ng.h/mL)、Cmax (1047 vs 1042 μg/mL)、t1/2 (2.25 vs 2.25 h)， Tmax中位数均为2 h。经方差分析和90% CI分析，制剂具有生物等效性。未检测到配方、周期、顺序和残留影响。不良事件轻微，耐受性良好，发作频率低。最常见的事件是高血压、头痛、转氨酶和尿素值升高，不到10%的受试者登记。结论:古巴双氯芬酸钠缓释制剂与市售参比制剂volaren Retard®具有生物等效性。
{"title":"Bioequivalence of Two Prolonged-Release Diclofenac Sodium Formulations in Healthy Volunteers: A Randomized, Crossover, Double-Blind Study","authors":"C. A. González-Delgado, Padrón-Yaquis As, Daise Jiménez-Rodríguez, D. Cazanave-Guarnaluce, Alejo-Cisneros Pl, Tatiana Festary-Casanovas, M. Barrios-Sarmiento, Alina Díaz-Machado, Sonia Pérez-Rodríguez, Alis Martín-Trujillo, L. Barrero-Viera, I. García-García","doi":"10.4172/jbb.1000361","DOIUrl":"https://doi.org/10.4172/jbb.1000361","url":null,"abstract":"Background: The implementation of generic drug development programs constitutes a basic component of the global health policy. The aim of this work is to determine the existence of bioequivalence between two prolonged release diclofenac sodium formulations in healthy volunteers. \u0000Methods: A phase I, randomized, crossover, double-blind clinical trial was conducted where pharmacokinetics in plasma and biological safety of Voltaren Retard® (reference formulation) and a generic prolonged-release Cuban diclofenac sodium formulation were compared. The sampling period was 24 hours, with a washout time of 15 days between each one. All subjects received, orally, a single dose of 100 mg (one tablet) of the corresponding formulation in each period. \u0000Results: Thirty-six volunteers, the half women, with a mean age of 33 years were included. White skin subjects were 56%. The quantification of diclofenac sodium in plasma by HPLC demonstrated a high similitude between formulations. The mean values of the pharmacokinetic parameters were: AUC24 (4924 vs. 4928 ng.h/mL), AUCinf (5046 vs. 5054 ng.h/mL), Cmax (1047 vs. 1042 μg/mL), t1/2 2.25 vs. 2.25 h), Median Tmax was 2 hours for both formulations. The preparations could be considered as bioequivalent according to ANOVA and 90% CI analysis. No formulation, period, sequential and residual effects were detected. The adverse events were mild, well tolerated, with a low frequency of onset. The most frequent events were hypertension, headache and increase in transaminases and urea values, registered in less than 10% of the subjects. \u0000Conclusion: Cuban prolonged-release diclofenac sodium formulation was bioequivalent with the commercial reference formulation Voltaren Retard®.","PeriodicalId":15184,"journal":{"name":"Journal of Bioequivalence & Bioavailability","volume":"23 1","pages":"555-560"},"PeriodicalIF":0.0,"publicationDate":"2017-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90814301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To define a chemical reaction, interactions between electrophiles and nucleophiles have paramount importance. The charge transfer between electrophiles and nucleophiles provides an insight to explain chemical behaviour. This kind of behavior is generally explained in terms of reactivity descriptors viz. electrophilicity index, global hardness etc. In the present report, we have tried to define electrophilicity index in force model. Though a number of scientists have already defined electrophilicity index in energy unit, definition of electrophilicity index in force model is yet to be explored. We have computed atomic electrophilicity index in force unit invoking following ansatz: ω=χ2/2η Where electronegativity (χ) and global hardness (η) both are defined in force unit. Our atomic data exhibits all sine qua non of periodic properties. Secondly, an attempt has been made to establish electrophilicity equalization principle and to compute molecular electrophilicity index through geometric mean equalization principle. Finally, we have attempted to correlate experimental toxicological properties in terms of our computed molecular electrophilicity index. 252 organic molecules with diverse toxicity have been modeled invoking our molecular electrophilicity index. A close agreement between experimental toxicity and our predicted data transpires the efficacy of our model.
{"title":"Molecular Electrophilicity Index - A Promising Descriptor for Predicting Toxicological Property","authors":"Tandon H, Chakraborty T, Shalini A","doi":"10.4172/JBB.1000356","DOIUrl":"https://doi.org/10.4172/JBB.1000356","url":null,"abstract":"To define a chemical reaction, interactions between electrophiles and nucleophiles have paramount importance. The charge transfer between electrophiles and nucleophiles provides an insight to explain chemical behaviour. This kind of behavior is generally explained in terms of reactivity descriptors viz. electrophilicity index, global hardness etc. In the present report, we have tried to define electrophilicity index in force model. Though a number of scientists have already defined electrophilicity index in energy unit, definition of electrophilicity index in force model is yet to be explored. We have computed atomic electrophilicity index in force unit invoking following ansatz: \u0000ω=χ2/2η \u0000Where electronegativity (χ) and global hardness (η) both are defined in force unit. Our atomic data exhibits all sine qua non of periodic properties. Secondly, an attempt has been made to establish electrophilicity equalization principle and to compute molecular electrophilicity index through geometric mean equalization principle. Finally, we have attempted to correlate experimental toxicological properties in terms of our computed molecular electrophilicity index. 252 organic molecules with diverse toxicity have been modeled invoking our molecular electrophilicity index. A close agreement between experimental toxicity and our predicted data transpires the efficacy of our model.","PeriodicalId":15184,"journal":{"name":"Journal of Bioequivalence & Bioavailability","volume":"24 1","pages":"518-527"},"PeriodicalIF":0.0,"publicationDate":"2017-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91245185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Badr Aljohani, F. FaisalAlotaibi, E. Ghazaly, J. Jaber, D. Perrett, A. Johnston
Ciclosporin is used as an immunosuppressant in post-organ transplantation. Recently, many questions have been raised about using generic substitutes, especially with narrow therapeutic index drugs (NTIDs). In this study, a simple high-performance liquid chromatography (HPLC) method was developed, validated and applied to detection ciclosporin in dissolution testing. Seven ciclosporin products (gelatin capsules) were included in this study, obtained from Columbia (C), Egypt (E), India (I), Jordan (J), Pakistan (P), Saudi Arabia (S), and Turkey (T). The dissolution test was done for all capsules. The Conditions were as follows: 500 ml deionized water as the medium in apparatus 2 (Pharmatest, Germany), temperature 37.5 ± 0.5°C; 50 rev/min, sampling times were 5, 10, 15, 30, 60 and 90 min with 5 ml for each sample. HPLC separation was done by a C18 column, 5 μm, (4.6 × 250 mm, ACE 5) held at 50 ± 0.3°C. Analytes were isocratically eluted at 0.7 ml/min with acetonitrile and water (70+30%) and 0.03% trifluoroacetic acid, over the 25-min run time. The intra-day and inter-day imprecision for ciclosporin across the standard range was <5% and <4%, respectively. The accuracy of the assay was within ± 13% of the true value at standard curve concentrations range from 0.1 to 2 mg/ml of ciclosporin. The lower and the upper limit of detection were 0.001 mg/ ml and 2 mg/ml of ciclosporin, respectively. All brands (S, T, P, J, E) and one generic (C) showed more than 80% of ciclosporin after 90 min (90.3, 100, 90.4, 82.7, 81.4 and 90.6%) respectively. One generic (I), showed less than the minimum percentage of labeled amount, 69.1%. Relative to the brand (T), statistical analysis showed significant differences (P<0.0001) of the mean percentage content between brand and generic. The 95% confidence interval range for the brands (E, J, P, and S) was (72.2-91.8), (73.4-93.3), (80.2-101.9), and (80.1-101.8), respectively, and (80.3-102.1), and (61.3-77.9) for the generic (C) and (I) respectively. Based on these results, we conclude that some of the ciclosporin preparations do not contain the exact mass labeled and the majority contained as yet unidentified impurities.
{"title":"Development and Validation of A HPLC-UV Method for Dissolution Testing of Ciclosporin: Its Application to The Measurement of Brand and Generic Versions from Different Countries","authors":"Badr Aljohani, F. FaisalAlotaibi, E. Ghazaly, J. Jaber, D. Perrett, A. Johnston","doi":"10.4172/JBB.1000354","DOIUrl":"https://doi.org/10.4172/JBB.1000354","url":null,"abstract":"Ciclosporin is used as an immunosuppressant in post-organ transplantation. Recently, many questions have been raised about using generic substitutes, especially with narrow therapeutic index drugs (NTIDs). In this study, a simple high-performance liquid chromatography (HPLC) method was developed, validated and applied to detection ciclosporin in dissolution testing. Seven ciclosporin products (gelatin capsules) were included in this study, obtained from Columbia (C), Egypt (E), India (I), Jordan (J), Pakistan (P), Saudi Arabia (S), and Turkey (T). The dissolution test was done for all capsules. The Conditions were as follows: 500 ml deionized water as the medium in apparatus 2 (Pharmatest, Germany), temperature 37.5 ± 0.5°C; 50 rev/min, sampling times were 5, 10, 15, 30, 60 and 90 min with 5 ml for each sample. HPLC separation was done by a C18 column, 5 μm, (4.6 × 250 mm, ACE 5) held at 50 ± 0.3°C. Analytes were isocratically eluted at 0.7 ml/min with acetonitrile and water (70+30%) and 0.03% trifluoroacetic acid, over the 25-min run time. The intra-day and inter-day imprecision for ciclosporin across the standard range was <5% and <4%, respectively. The accuracy of the assay was within ± 13% of the true value at standard curve concentrations range from 0.1 to 2 mg/ml of ciclosporin. The lower and the upper limit of detection were 0.001 mg/ ml and 2 mg/ml of ciclosporin, respectively. All brands (S, T, P, J, E) and one generic (C) showed more than 80% of ciclosporin after 90 min (90.3, 100, 90.4, 82.7, 81.4 and 90.6%) respectively. One generic (I), showed less than the minimum percentage of labeled amount, 69.1%. Relative to the brand (T), statistical analysis showed significant differences (P<0.0001) of the mean percentage content between brand and generic. The 95% confidence interval range for the brands (E, J, P, and S) was (72.2-91.8), (73.4-93.3), (80.2-101.9), and (80.1-101.8), respectively, and (80.3-102.1), and (61.3-77.9) for the generic (C) and (I) respectively. Based on these results, we conclude that some of the ciclosporin preparations do not contain the exact mass labeled and the majority contained as yet unidentified impurities.","PeriodicalId":15184,"journal":{"name":"Journal of Bioequivalence & Bioavailability","volume":"23 1","pages":"509-515"},"PeriodicalIF":0.0,"publicationDate":"2017-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74512167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-09-11DOI: 10.4172/0975-0851-C1-029
Shyam B. Mehta
{"title":"A case study on manufacturing issues during processing of a lyophilized drug product","authors":"Shyam B. Mehta","doi":"10.4172/0975-0851-C1-029","DOIUrl":"https://doi.org/10.4172/0975-0851-C1-029","url":null,"abstract":"","PeriodicalId":15184,"journal":{"name":"Journal of Bioequivalence & Bioavailability","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89081181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yerino Ga, Feleder Ec, Otero Am, D. L, Sakson M, Mondelo N, Roldán Eja
Background: Perampanel is a glutamate non-competitive receptor antagonist that is effective as adjunctive treatment for epilepsy. No studies regarding comparative bioavailability between a generic perampanel formulation and the brand-name product have been published in the literature. Therefore, the goal of the present investigation was to compare the bioavailability and to evaluate the bioequivalence between a novel pharmaceutical equivalent 12 mg film-coated tablet formulation and the reference product. Methods: An open label, randomized-sequence, two-period, two-treatment, single-dose, crossover design study in healthy volunteers(n=24) was conducted. The treatment was split out by a 42 days wash-out period. The informed consent was signed by all volunteers. Healthy subjects of both genders, including non-pregnant and nonlactating females between 21-55 years with Quetelet index between 19-29 kg/m2 were enrolled. Blood samples were withdrawn in vacutainers with EDTA over 168 h and plasma levels of perampanel were measured by HPLC/ fluorescence method. Pharmacokinetic (PK) variables (Cmax, AUC0-last, and AUCinf) after a single oral administration dose of the test and reference treatments were analyzed by a non-compartmental PK model using natural logtransformed data and were compared by ANOVA for a two-treatment crossover design. Bioequivalence between the two formulations was evaluated using the 90% Confidence Interval (CI) comprised between 80-125% corresponding to the ratio of the geometric means for log-transformed PK parameters. Results: A similar bioavailability between products was determined. Test and reference formulations showed no statistically significant differences in relation to the fixed effect of period, sequence, treatment and volunteers within sequence as random effect for PK variables. The estimated point and 90% CI of the ratios of Cmax, AUC0-last and AUCinf were 0.92 (0.83-1.03), 1.04(0.98-1.10) and 0.98 (0.86-1.11), respectively. The formulations showed comparable safety and tolerability. Conclusion: The new pharmaceutical equivalent perampanel 12 mg film-coated tablet formulation was also bioequivalent to the reference product. Therefore, both drugs are interchangeable.
{"title":"Comparative Bioavailability of Two Oral Perampanel Formulations in Healthy Subjects: A Randomized, Open Label, Single-Dose, 2-Way Crossover Study","authors":"Yerino Ga, Feleder Ec, Otero Am, D. L, Sakson M, Mondelo N, Roldán Eja","doi":"10.4172/JBB.1000353","DOIUrl":"https://doi.org/10.4172/JBB.1000353","url":null,"abstract":"Background: Perampanel is a glutamate non-competitive receptor antagonist that is effective as adjunctive treatment for epilepsy. No studies regarding comparative bioavailability between a generic perampanel formulation and the brand-name product have been published in the literature. Therefore, the goal of the present investigation was to compare the bioavailability and to evaluate the bioequivalence between a novel pharmaceutical equivalent 12 mg film-coated tablet formulation and the reference product. \u0000 \u0000Methods: An open label, randomized-sequence, two-period, two-treatment, single-dose, crossover design study in healthy volunteers(n=24) was conducted. The treatment was split out by a 42 days wash-out period. The informed consent was signed by all volunteers. Healthy subjects of both genders, including non-pregnant and nonlactating females between 21-55 years with Quetelet index between 19-29 kg/m2 were enrolled. Blood samples were withdrawn in vacutainers with EDTA over 168 h and plasma levels of perampanel were measured by HPLC/ fluorescence method. Pharmacokinetic (PK) variables (Cmax, AUC0-last, and AUCinf) after a single oral administration dose of the test and reference treatments were analyzed by a non-compartmental PK model using natural logtransformed data and were compared by ANOVA for a two-treatment crossover design. Bioequivalence between the two formulations was evaluated using the 90% Confidence Interval (CI) comprised between 80-125% corresponding to the ratio of the geometric means for log-transformed PK parameters. \u0000 \u0000Results: A similar bioavailability between products was determined. Test and reference formulations showed no statistically significant differences in relation to the fixed effect of period, sequence, treatment and volunteers within sequence as random effect for PK variables. The estimated point and 90% CI of the ratios of Cmax, AUC0-last and AUCinf were 0.92 (0.83-1.03), 1.04(0.98-1.10) and 0.98 (0.86-1.11), respectively. The formulations showed comparable safety and tolerability. \u0000 \u0000Conclusion: The new pharmaceutical equivalent perampanel 12 mg film-coated tablet formulation was also bioequivalent to the reference product. Therefore, both drugs are interchangeable.","PeriodicalId":15184,"journal":{"name":"Journal of Bioequivalence & Bioavailability","volume":"41 1","pages":"501-508"},"PeriodicalIF":0.0,"publicationDate":"2017-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78378779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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