Pub Date : 2020-12-11DOI: 10.30895/1991-2919-2020-10-4-257-266
E. Bondareva, K. E. Borovkova, M. Makarova
The paper discusses the system of managing risks arising during preclinical studies (risks for the health of personnel and laboratory animals, as well as risks associated with sanitation of premises) as a way to improve and control the efficiency of processes and the safety of facilities involved in preclinical studies.The aim of the study was to analyse the risk assessment system’s efficiency for improvement of drug safety assessment during preclinical studies in the context of animal care and use programmes.Materials and methods: the Failure Mode Effect Analysis (FMEA) method was used to assess the sanitary and hygienic conditions in laboratory animal facilities, as well as health status and welfare of laboratory animals and the attending personnel. The study checked the presence of pathogenic and opportunistic microflora as the main potential inconsistencies.Results: the risk assessment performed during monitoring of laboratory animal health, monitoring of surface cleanliness, and assessment of personnel health, helped to establish a list of the most dangerous pathogens that require stricter control. In order to reduce risks arising during preclinical studies, the following set of measures was proposed: monitoring of the living environment and health of laboratory animals, revision of therapeutic and preventive measures for laboratory animals (including adjustment of antibiotic treatment depending on antimicrobial resistance of microorganisms), monitoring of the personnel health status, taking measures to enhance the personnel vigilance with respect to their own health, prohibition to work at the premises for employees showing symptoms, control of how the employees showing symptoms observe the prohibition to work at the premises, organisation of periodic medical examinations for personnel having contact with laboratory animals.Conclusions: the risk-based assessment helped to identify the most dangerous potential inconsistencies (pathogenic and opportunistic microflora) and the necessary preventive measures to control and manage potential risk consequences.
{"title":"Risk-Based Approach to the Assessment of Sanitary Safety of Vivariums and Breeding Facilities, and Health Status of Personnel and Laboratory Animals","authors":"E. Bondareva, K. E. Borovkova, M. Makarova","doi":"10.30895/1991-2919-2020-10-4-257-266","DOIUrl":"https://doi.org/10.30895/1991-2919-2020-10-4-257-266","url":null,"abstract":"The paper discusses the system of managing risks arising during preclinical studies (risks for the health of personnel and laboratory animals, as well as risks associated with sanitation of premises) as a way to improve and control the efficiency of processes and the safety of facilities involved in preclinical studies.The aim of the study was to analyse the risk assessment system’s efficiency for improvement of drug safety assessment during preclinical studies in the context of animal care and use programmes.Materials and methods: the Failure Mode Effect Analysis (FMEA) method was used to assess the sanitary and hygienic conditions in laboratory animal facilities, as well as health status and welfare of laboratory animals and the attending personnel. The study checked the presence of pathogenic and opportunistic microflora as the main potential inconsistencies.Results: the risk assessment performed during monitoring of laboratory animal health, monitoring of surface cleanliness, and assessment of personnel health, helped to establish a list of the most dangerous pathogens that require stricter control. In order to reduce risks arising during preclinical studies, the following set of measures was proposed: monitoring of the living environment and health of laboratory animals, revision of therapeutic and preventive measures for laboratory animals (including adjustment of antibiotic treatment depending on antimicrobial resistance of microorganisms), monitoring of the personnel health status, taking measures to enhance the personnel vigilance with respect to their own health, prohibition to work at the premises for employees showing symptoms, control of how the employees showing symptoms observe the prohibition to work at the premises, organisation of periodic medical examinations for personnel having contact with laboratory animals.Conclusions: the risk-based assessment helped to identify the most dangerous potential inconsistencies (pathogenic and opportunistic microflora) and the necessary preventive measures to control and manage potential risk consequences.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"54 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90857180","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 : 2020-12-11DOI: 10.30895/1991-2919-2020-10-4-244-256
A. Malysheva, G. Kodina, E. A. Lyamtseva, N. A. Taratonenkova, A. Lunev
Most important quality attributes of any radiopharmaceutical (RPh) are its radiochemical purity (RCP) or content of radiochemical impurities (RCIs) that have to comply with respective norms and limits. However, at present, there is no unified approach to validation of analytical methods in the context of highly radioactive samples.The aim of the study was to develop an approach to validation of methods for determination of RCI content in RPhs.Materials and methods: the authors determined the content of RCIs in a radiopharmaceutical formulation containing a complex of technetium-99m and methylenediphosphonic acid by the radiometric method after isolation of impurities from the main compound by thin-layer chromatography using silica gel and methyl ethyl ketone (for sodium pertechnetate determination) and silica gel and 13.6% sodium acetate solution (for determination of hydrolysed reduced technetium-99m). The radioactivity was registered by a chromatogram scanner with a detector of gamma-rays with energies from 0.05 to 1.5 MeV.Results: the paper analyses existing official approaches to validation of analytical procedures and compares them with the results of experimental studies described in available publications. It assesses the validation parameters for compliance with the acceptance criteria set forth in the current regulations and substantiates selectivity of chromatographic determination of impurities under the selected test conditions. Coefficients of variation for repeatability, reproducibility, and accuracy did not exceed 4.5, 2.8, and 8.9%, respectively, given the relative error of not more than 10.5%. The study demonstrated signal linearity for the 10-fold dilution of the standardised sodium pertechnetate solution, it also demonstrated correspondence between the applied and detected radioactivity when performing the test in the impurity content range of 0.5–5%. The validation procedure was associated with significant radiation burden for the personnel of the quality control laboratory.Conclusions: the authors suggested a methodological approach to validation of methods for determination of RCI content in technetium-99m-based RPhs. This approach may be used in the development of a guideline on validation of analytical methods for RCP/RCI determination in RPhs, or for introduction of relevant sections into existing documents.
{"title":"Experience in Validation of Methods for Determination of Radiochemical Impurities in Radiopharmaceuticals","authors":"A. Malysheva, G. Kodina, E. A. Lyamtseva, N. A. Taratonenkova, A. Lunev","doi":"10.30895/1991-2919-2020-10-4-244-256","DOIUrl":"https://doi.org/10.30895/1991-2919-2020-10-4-244-256","url":null,"abstract":"Most important quality attributes of any radiopharmaceutical (RPh) are its radiochemical purity (RCP) or content of radiochemical impurities (RCIs) that have to comply with respective norms and limits. However, at present, there is no unified approach to validation of analytical methods in the context of highly radioactive samples.The aim of the study was to develop an approach to validation of methods for determination of RCI content in RPhs.Materials and methods: the authors determined the content of RCIs in a radiopharmaceutical formulation containing a complex of technetium-99m and methylenediphosphonic acid by the radiometric method after isolation of impurities from the main compound by thin-layer chromatography using silica gel and methyl ethyl ketone (for sodium pertechnetate determination) and silica gel and 13.6% sodium acetate solution (for determination of hydrolysed reduced technetium-99m). The radioactivity was registered by a chromatogram scanner with a detector of gamma-rays with energies from 0.05 to 1.5 MeV.Results: the paper analyses existing official approaches to validation of analytical procedures and compares them with the results of experimental studies described in available publications. It assesses the validation parameters for compliance with the acceptance criteria set forth in the current regulations and substantiates selectivity of chromatographic determination of impurities under the selected test conditions. Coefficients of variation for repeatability, reproducibility, and accuracy did not exceed 4.5, 2.8, and 8.9%, respectively, given the relative error of not more than 10.5%. The study demonstrated signal linearity for the 10-fold dilution of the standardised sodium pertechnetate solution, it also demonstrated correspondence between the applied and detected radioactivity when performing the test in the impurity content range of 0.5–5%. The validation procedure was associated with significant radiation burden for the personnel of the quality control laboratory.Conclusions: the authors suggested a methodological approach to validation of methods for determination of RCI content in technetium-99m-based RPhs. This approach may be used in the development of a guideline on validation of analytical methods for RCP/RCI determination in RPhs, or for introduction of relevant sections into existing documents.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"82 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88684183","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 : 2020-11-20DOI: 10.30895/1991-2919-2020-10-4-236-243
A. Solodovnikov, E. Sorokina, E. Morkovin
Idiopathic thrombocytopenic purpura (ITP), or primary immune thrombocytopenia, is an orphan disease associated with thrombocytopenia. One of the most recent and promising approaches to ITP treatment is the use of thrombopoietin receptor agonists (TPO-RAs). The scope of TPO-RA use is expanding rapidly, which stimulates the development of both innovator and generic (or biosimilar) medicines. The aim of the paper was to assess TPO-RA role in ITP treatment, methodological approaches to TPO-RA development, and feasibility of using the platelet count as a pharmacodynamic marker in bioequivalence studies of peptide TPO-RAs in healthy volunteers. Clinical development of new medicines for the treatment of thrombocytopenia includes comparative, parallel-group trials lasting about a year. The standard approach to bioequivalence studies, which is based on the results of comparative pharmacokinetic studies, can be used in marketing authorisation applications for generic non-peptide TPO agonists, while peptide TPO agonists have to comply with specific requirements for biosimilar products. The orphan status of ITP does not affect the development strategy and study design, but it limits the number of patients that could be included into the study. In the absence of valid surrogate biomarkers of efficacy, demonstration of comparable clinical efficacy of the biosimilar and reference drug is usually required in a randomised, parallel, preferably double-blind comparative study. On the other hand, clinical comparability of the biosimilar and reference drug can also be demonstrated in comparative pharmacodynamic studies, if the selected biomarker is a well-established and valid surrogate marker which correlates with patient clinical outcome. Platelet count is a key parameter in both diagnosis of diseases associated with low platelet levels and assessment of treatment efficacy. Therefore, it can be used as a pharmacodynamic marker in bioequivalence studies of biosimilar peptide TPO-RAs. It was concluded that such studies could be performed in healthy volunteers, and not in patients, whose participation in clinical trials is limited due to the orphan status of ITP.
{"title":"Thrombopoietin Receptor Agonists: Clinical Use and Evaluation of Treatment Efficacy","authors":"A. Solodovnikov, E. Sorokina, E. Morkovin","doi":"10.30895/1991-2919-2020-10-4-236-243","DOIUrl":"https://doi.org/10.30895/1991-2919-2020-10-4-236-243","url":null,"abstract":"Idiopathic thrombocytopenic purpura (ITP), or primary immune thrombocytopenia, is an orphan disease associated with thrombocytopenia. One of the most recent and promising approaches to ITP treatment is the use of thrombopoietin receptor agonists (TPO-RAs). The scope of TPO-RA use is expanding rapidly, which stimulates the development of both innovator and generic (or biosimilar) medicines. The aim of the paper was to assess TPO-RA role in ITP treatment, methodological approaches to TPO-RA development, and feasibility of using the platelet count as a pharmacodynamic marker in bioequivalence studies of peptide TPO-RAs in healthy volunteers. Clinical development of new medicines for the treatment of thrombocytopenia includes comparative, parallel-group trials lasting about a year. The standard approach to bioequivalence studies, which is based on the results of comparative pharmacokinetic studies, can be used in marketing authorisation applications for generic non-peptide TPO agonists, while peptide TPO agonists have to comply with specific requirements for biosimilar products. The orphan status of ITP does not affect the development strategy and study design, but it limits the number of patients that could be included into the study. In the absence of valid surrogate biomarkers of efficacy, demonstration of comparable clinical efficacy of the biosimilar and reference drug is usually required in a randomised, parallel, preferably double-blind comparative study. On the other hand, clinical comparability of the biosimilar and reference drug can also be demonstrated in comparative pharmacodynamic studies, if the selected biomarker is a well-established and valid surrogate marker which correlates with patient clinical outcome. Platelet count is a key parameter in both diagnosis of diseases associated with low platelet levels and assessment of treatment efficacy. Therefore, it can be used as a pharmacodynamic marker in bioequivalence studies of biosimilar peptide TPO-RAs. It was concluded that such studies could be performed in healthy volunteers, and not in patients, whose participation in clinical trials is limited due to the orphan status of ITP.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"67 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90199586","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 : 2020-09-18DOI: 10.30895/1991-2919-2020-10-3-152-163
D. Goryachev, N. E. Uvarova, G. V. Shukshina
No new drug can be used in clinical practice without marketing authorisation. Acquisition of the necessary amount of clinical data may take several years, which is especially critical for pernicious diseases for which no alternative therapy is available. Lack of treatment options creates conditions in which early introduction of efficacious therapy into clinical practice is becoming crucial. This need resulted in the development of new regulatory approaches aimed at accelerated approval of drugs both by reducing the time frame and by fulfilling post-authorisation requirements. The aim of the study was to review regulatory approaches to the accelerated authorisation procedure based on incomplete clinical data, and analyse their potential use in the Russian Federation. The paper presents an overview of authorisation pathways based on incomplete clinical data, which are used by different regulatory authorities, as well as regulatory approaches used in the Eurasian Economic Union (EAEU) and as part of the Russian national authorisation procedure. It was demonstrated that the approaches used by the US, European, and Japanese regulatory authorities, despite some differences, share a common objective of accelerated approval of drugs that fill an unmet medical need. The EAEU also has a conditional approval procedure, but the proposed criteria do not make it possible to use this approach in a real clinical situation of an unmet medical need. A similar national procedure would make it possible to reach a compromise between the needs of the healthcare system and the sound basis for informed decisions of the regulatory authority. Accelerated introduction of novel drugs that address unmet medical needs would set the national regulation in the area of drug circulation on the right track.
{"title":"Marketing Authorisation Based on Incomplete Clinical Data: International Experience and Prospects","authors":"D. Goryachev, N. E. Uvarova, G. V. Shukshina","doi":"10.30895/1991-2919-2020-10-3-152-163","DOIUrl":"https://doi.org/10.30895/1991-2919-2020-10-3-152-163","url":null,"abstract":"No new drug can be used in clinical practice without marketing authorisation. Acquisition of the necessary amount of clinical data may take several years, which is especially critical for pernicious diseases for which no alternative therapy is available. Lack of treatment options creates conditions in which early introduction of efficacious therapy into clinical practice is becoming crucial. This need resulted in the development of new regulatory approaches aimed at accelerated approval of drugs both by reducing the time frame and by fulfilling post-authorisation requirements. The aim of the study was to review regulatory approaches to the accelerated authorisation procedure based on incomplete clinical data, and analyse their potential use in the Russian Federation. The paper presents an overview of authorisation pathways based on incomplete clinical data, which are used by different regulatory authorities, as well as regulatory approaches used in the Eurasian Economic Union (EAEU) and as part of the Russian national authorisation procedure. It was demonstrated that the approaches used by the US, European, and Japanese regulatory authorities, despite some differences, share a common objective of accelerated approval of drugs that fill an unmet medical need. The EAEU also has a conditional approval procedure, but the proposed criteria do not make it possible to use this approach in a real clinical situation of an unmet medical need. A similar national procedure would make it possible to reach a compromise between the needs of the healthcare system and the sound basis for informed decisions of the regulatory authority. Accelerated introduction of novel drugs that address unmet medical needs would set the national regulation in the area of drug circulation on the right track.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84318471","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 : 2020-09-18DOI: 10.30895/1991-2919-2020-10-3-177-183
I. A. Mazerkina, V. Evteev, A. Prokofiev, O. V. Muslimova, E. Demchenkova
Organic anion transporters OAT1 and OAT3 play a key role in elimination of most β-lactam antibiotics. Since nonsteroidal anti-inflammatory drugs, antivirals, antitumor agents, and some other drugs are also substrates of OAT1/3, this enables drug-drug interaction (DDI). The aim of the study was to analyze scientific literature to determine the likelihood and significance of β-lactam antibiotic DDI mediated by organic anion transporters, as well as potential for predicting it. In clinical practice, inhibition of β-lactam antibiotic elimination is used to increase systemic exposition and reduce the cost of antibiotic therapy. OAT inhibitors (cilastatin, betamipron) are used in combination drugs to reduce nephrotoxicity of carbapenems. On the other hand, an increase in the concentration of β-lactams due to OAT inhibition may lead to adverse drug reactions. Therefore, the European Medicines Agency and the Food and Drug Administration recommendations for the development of new drugs state that in the case of significant renal excretion (≥25%) it is necessary to investigate OAT1/3 transport in vitro and calculate inhibition constant Ki and/or half maximal inhibitory concentration IC50 for predicting DDI. One of the main problems is the variability of Ki and IC50 values between laboratories, which requires the development of general recommendations for different transporters as regards methods of determination of these parameters.
有机阴离子转运体OAT1和OAT3在消除大多数β-内酰胺类抗生素中起关键作用。由于非甾体类抗炎药、抗病毒药物、抗肿瘤药物和其他一些药物也是OAT1/3的底物，这使得药物-药物相互作用(DDI)成为可能。本研究的目的是通过分析科学文献来确定有机阴离子转运体介导β-内酰胺类抗生素DDI的可能性和意义，以及预测它的潜力。在临床实践中，抑制β-内酰胺类抗生素消除被用于增加全身暴露和降低抗生素治疗的成本。OAT抑制剂(西司他汀，倍他米酮)用于联合用药以降低碳青霉烯类药物的肾毒性。另一方面，由于OAT抑制，β-内酰胺的浓度增加可能导致药物不良反应。因此，欧洲药品管理局(European Medicines Agency)和美国食品和药物管理局(Food and Drug Administration)的新药开发建议指出，在肾排泄显著(≥25%)的情况下，有必要研究ooat1 /3的体外转运，并计算抑制常数Ki和/或一半最大抑制浓度IC50，以预测DDI。其中一个主要问题是实验室之间Ki和IC50值的可变性，这就需要针对不同的转运体制定确定这些参数的方法的一般建议。
{"title":"β-Lactam Antibiotics—Drug-Drug Interaction Mediated by Organic Anion Transporters OAT1 and OAT3","authors":"I. A. Mazerkina, V. Evteev, A. Prokofiev, O. V. Muslimova, E. Demchenkova","doi":"10.30895/1991-2919-2020-10-3-177-183","DOIUrl":"https://doi.org/10.30895/1991-2919-2020-10-3-177-183","url":null,"abstract":"Organic anion transporters OAT1 and OAT3 play a key role in elimination of most β-lactam antibiotics. Since nonsteroidal anti-inflammatory drugs, antivirals, antitumor agents, and some other drugs are also substrates of OAT1/3, this enables drug-drug interaction (DDI). The aim of the study was to analyze scientific literature to determine the likelihood and significance of β-lactam antibiotic DDI mediated by organic anion transporters, as well as potential for predicting it. In clinical practice, inhibition of β-lactam antibiotic elimination is used to increase systemic exposition and reduce the cost of antibiotic therapy. OAT inhibitors (cilastatin, betamipron) are used in combination drugs to reduce nephrotoxicity of carbapenems. On the other hand, an increase in the concentration of β-lactams due to OAT inhibition may lead to adverse drug reactions. Therefore, the European Medicines Agency and the Food and Drug Administration recommendations for the development of new drugs state that in the case of significant renal excretion (≥25%) it is necessary to investigate OAT1/3 transport in vitro and calculate inhibition constant Ki and/or half maximal inhibitory concentration IC50 for predicting DDI. One of the main problems is the variability of Ki and IC50 values between laboratories, which requires the development of general recommendations for different transporters as regards methods of determination of these parameters.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82075145","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 : 2020-09-18DOI: 10.30895/1991-2919-2020-10-3-192-200
G. G. Rodionov, I. Shantyr, I. E. Ushal, E. V. Svetkina, E. Kolobova, K. Zakharov
ИЭ, Светкина ЕВ, Колобова ЕА, КА. ВЭЖХ-МС/МС мето- определения силденафила и его в Abstract. A high demand for sildenafil-based drugs puts a premium on the development of methods for quantitation of sildenafil in bio-substrates to facilitate pharmacokinetic analysis in bioequivalence studies. High performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) was proposed for the method development due to its high sensitivity, selectivity, reproducibility, and performance. The aim of the study was to develop and validate an HPLC-MS/MS method for quantitative determination of sildenafil and its active metabolite N-desmethyl sildenafil in human plasma. Approbation of the developed tech- nique in the study of the pharmacokinetic profiles of sildenafil and N-desmethyl sildenafil in healthy volunteers in the study of the bioequivalence of the drug sildenafil in the form of a spray. Materials and methods: the method was implemented using the Agilent 1200 high-performance liquid chromatography system with the Agilent 6440 triple quadrupole system, and Poroshell 120 EC-C18 chromatographic column, 4.6 m × 1 50 mm × 2.7 μm. Calibration samples were prepared using sildenafil citrate and N-desmethyl sildenafil reference standards with 99.5 and 98.5% purity, respectively. Vardenafil was used as an internal standard. Pharmacoki- netic profiles of sildenafil and N-desmethyl sildenafil were studied in 44 healthy male volunteers as part of a bioequivalence study approved by the Ministry of Health of the Russian Federation. The primary data processing was performed using Mass Hunter software version B 06.00, and statistical processing was performed using Microsoft Office Excel 2010 and Statistica 6.1. Results: the authors developed and validated a method for quantitation of sildenafil and its active metabolite N-desmethyl sildenafil in human plasma. The developed method was used successfully to study pharmacokinetic profiles of the discussed compounds in healthy volunteers. Conclusions: the developed method of quantitative determination of sildenafil and its active metabolite N-des- methyl sildenafil in human plasma is simple, reproducible, fast, and robust. The results of the pharmacokinetic studies using the developed method demonstrated bioequivalence of the test product and the reference product.
{"title":"HPLC-MS/MS Method for Quantitation of Sildenafil and Its Active Metabolite in Human Plasma","authors":"G. G. Rodionov, I. Shantyr, I. E. Ushal, E. V. Svetkina, E. Kolobova, K. Zakharov","doi":"10.30895/1991-2919-2020-10-3-192-200","DOIUrl":"https://doi.org/10.30895/1991-2919-2020-10-3-192-200","url":null,"abstract":"ИЭ, Светкина ЕВ, Колобова ЕА, КА. ВЭЖХ-МС/МС мето- определения силденафила и его в Abstract. A high demand for sildenafil-based drugs puts a premium on the development of methods for quantitation of sildenafil in bio-substrates to facilitate pharmacokinetic analysis in bioequivalence studies. High performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) was proposed for the method development due to its high sensitivity, selectivity, reproducibility, and performance. The aim of the study was to develop and validate an HPLC-MS/MS method for quantitative determination of sildenafil and its active metabolite N-desmethyl sildenafil in human plasma. Approbation of the developed tech- nique in the study of the pharmacokinetic profiles of sildenafil and N-desmethyl sildenafil in healthy volunteers in the study of the bioequivalence of the drug sildenafil in the form of a spray. Materials and methods: the method was implemented using the Agilent 1200 high-performance liquid chromatography system with the Agilent 6440 triple quadrupole system, and Poroshell 120 EC-C18 chromatographic column, 4.6 m × 1 50 mm × 2.7 μm. Calibration samples were prepared using sildenafil citrate and N-desmethyl sildenafil reference standards with 99.5 and 98.5% purity, respectively. Vardenafil was used as an internal standard. Pharmacoki- netic profiles of sildenafil and N-desmethyl sildenafil were studied in 44 healthy male volunteers as part of a bioequivalence study approved by the Ministry of Health of the Russian Federation. The primary data processing was performed using Mass Hunter software version B 06.00, and statistical processing was performed using Microsoft Office Excel 2010 and Statistica 6.1. Results: the authors developed and validated a method for quantitation of sildenafil and its active metabolite N-desmethyl sildenafil in human plasma. The developed method was used successfully to study pharmacokinetic profiles of the discussed compounds in healthy volunteers. Conclusions: the developed method of quantitative determination of sildenafil and its active metabolite N-des- methyl sildenafil in human plasma is simple, reproducible, fast, and robust. The results of the pharmacokinetic studies using the developed method demonstrated bioequivalence of the test product and the reference product.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"77 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76812864","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 : 2020-09-18DOI: 10.30895/1991-2919-2020-10-3-184-191
Z. Shprakh
Open borders of the present-day pharmaceutical market call for improvement and harmonisation of the legal basis underlying drug circulation. Part of the overall process of harmonisation of regulatory requirements is the alignment of the terminological systems used in Russian and foreign pharmacopoeial and marketing authorisation-related activities. The aim of the study was to compare the Standard Terms database of the European Pharmacopoeia and corresponding documents of the Eurasian Economic Union. The paper describes the structure of the Standard Terms database of the European Pharmacopoeia and the Nomenclature of Dosage Forms adopted in the Eurasian Economic Union. It compares classifications applied at different levels of the pharmaceutical dosage form hierarchy. The paper summarises characteristics of the basic and additional elements forming the name of a pharmaceutical dosage form and cites some specific cases to illustrate the modern approaches to inventing such names. It demonstrates a high degree of conformity between the terminological systems and potential for their further convergence. The data provided can be used in the elaboration of pharmacopoeial texts for the State Pharmacopoeia of the Russian Federation, in the development of medicines, their authorisation, as well as for further convergence of the names of dosage forms used in the European and Eurasian markets.
{"title":"Harmonisation of Russian and Foreign Pharmacopoeial Standard Terms","authors":"Z. Shprakh","doi":"10.30895/1991-2919-2020-10-3-184-191","DOIUrl":"https://doi.org/10.30895/1991-2919-2020-10-3-184-191","url":null,"abstract":"Open borders of the present-day pharmaceutical market call for improvement and harmonisation of the legal basis underlying drug circulation. Part of the overall process of harmonisation of regulatory requirements is the alignment of the terminological systems used in Russian and foreign pharmacopoeial and marketing authorisation-related activities. The aim of the study was to compare the Standard Terms database of the European Pharmacopoeia and corresponding documents of the Eurasian Economic Union. The paper describes the structure of the Standard Terms database of the European Pharmacopoeia and the Nomenclature of Dosage Forms adopted in the Eurasian Economic Union. It compares classifications applied at different levels of the pharmaceutical dosage form hierarchy. The paper summarises characteristics of the basic and additional elements forming the name of a pharmaceutical dosage form and cites some specific cases to illustrate the modern approaches to inventing such names. It demonstrates a high degree of conformity between the terminological systems and potential for their further convergence. The data provided can be used in the elaboration of pharmacopoeial texts for the State Pharmacopoeia of the Russian Federation, in the development of medicines, their authorisation, as well as for further convergence of the names of dosage forms used in the European and Eurasian markets.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82040400","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 : 2020-09-18DOI: 10.30895/1991-2919-2020-10-3-212-212
A. Editorial
Neugodova N.P., Stepanyuk E.O., Sapozhnikova G.A., Sakanyan E.I., Ryabtseva M.S. Current approaches to the abnormal toxicity test. Vedomosti Nauchnogo tsentra ekspertizy sredstv meditsinskogo primeneniya = The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. 2020;10(2):82–88. https://doi.org/10.30895/1991-2919-2020-10-2-82-88Dear readers, on page 84 (second paragraph from the bottom, left column) in issue 2 of The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products, 2020 (2020;10(2):82–88) the following statement: “The discussions centered around suppression of the abnormal toxicity test and target animal batch safety test for vaccines for human use, and the possibility of suppression of the laboratory animal batch safety test for veterinary vaccines” should read: “The discussions centered around suppression of the abnormal toxicity test for vaccines for human use, and the possibility of suppression of the laboratory animal batch safety test and target animal batch safety test for veterinary vaccines”.
{"title":"Erratum: N.P. Neugodova et al., Current approaches to the abnormal toxicity test","authors":"A. Editorial","doi":"10.30895/1991-2919-2020-10-3-212-212","DOIUrl":"https://doi.org/10.30895/1991-2919-2020-10-3-212-212","url":null,"abstract":"Neugodova N.P., Stepanyuk E.O., Sapozhnikova G.A., Sakanyan E.I., Ryabtseva M.S. Current approaches to the abnormal toxicity test. Vedomosti Nauchnogo tsentra ekspertizy sredstv meditsinskogo primeneniya = The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. 2020;10(2):82–88. https://doi.org/10.30895/1991-2919-2020-10-2-82-88Dear readers, on page 84 (second paragraph from the bottom, left column) in issue 2 of The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products, 2020 (2020;10(2):82–88) the following statement: “The discussions centered around suppression of the abnormal toxicity test and target animal batch safety test for vaccines for human use, and the possibility of suppression of the laboratory animal batch safety test for veterinary vaccines” should read: “The discussions centered around suppression of the abnormal toxicity test for vaccines for human use, and the possibility of suppression of the laboratory animal batch safety test and target animal batch safety test for veterinary vaccines”. ","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"63 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77606558","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 : 2020-09-18DOI: 10.30895/1991-2919-2020-10-3-164-176
N. Eremina, L. Kolik, R. Ostrovskaya, A. Durnev
Neurotoxic effects are one of the common reasons for discontinuation of preclinical and/or clinical studies. Preclinical evaluation of neurotoxic effects is complicated due to a wide range of manifestations and degrees of severity. Current experimental approaches to neurotoxicity assessment are cumbersome, laborious and not adapted enough for preclinical studies in the early stages of drug development. The aim of the study was to review existing approaches to experimental assessment of neurotoxic potential of new drugs and to discuss the need for and feasibility of developing and using integrated rapid neurotoxicity tests for early assessment of a pharmacological project’s potential. The authors reviewed scientific literature and guidance documents and analysed current approaches to chemical compound neurotoxicity assessment in laboratory animals. The paper analyses the main issues of neurotoxicity assessment for new drugs and compares Irwin tests with the functional observation battery. It analyses issues related to assessment of drugs’ effects on the development and maturation of central nervous system functions at pre- and postnatal stages. It was determined that the current practice is not sufficient for assessment of potential adverse effects on cognitive functions. The authors assessed factors affecting cognitive functions of rodents during studies. The “Acute suppression of the exploratory and orientation response” and “Extrapolation escape task” tests were proposed for validation as potential rapid tests for detection of an array of organic and functional neurotoxic disorders at early stages of preclinical studies.
{"title":"Preclinical in vivo Neurotoxicity Studies of Drug Candidates","authors":"N. Eremina, L. Kolik, R. Ostrovskaya, A. Durnev","doi":"10.30895/1991-2919-2020-10-3-164-176","DOIUrl":"https://doi.org/10.30895/1991-2919-2020-10-3-164-176","url":null,"abstract":"Neurotoxic effects are one of the common reasons for discontinuation of preclinical and/or clinical studies. Preclinical evaluation of neurotoxic effects is complicated due to a wide range of manifestations and degrees of severity. Current experimental approaches to neurotoxicity assessment are cumbersome, laborious and not adapted enough for preclinical studies in the early stages of drug development. The aim of the study was to review existing approaches to experimental assessment of neurotoxic potential of new drugs and to discuss the need for and feasibility of developing and using integrated rapid neurotoxicity tests for early assessment of a pharmacological project’s potential. The authors reviewed scientific literature and guidance documents and analysed current approaches to chemical compound neurotoxicity assessment in laboratory animals. The paper analyses the main issues of neurotoxicity assessment for new drugs and compares Irwin tests with the functional observation battery. It analyses issues related to assessment of drugs’ effects on the development and maturation of central nervous system functions at pre- and postnatal stages. It was determined that the current practice is not sufficient for assessment of potential adverse effects on cognitive functions. The authors assessed factors affecting cognitive functions of rodents during studies. The “Acute suppression of the exploratory and orientation response” and “Extrapolation escape task” tests were proposed for validation as potential rapid tests for detection of an array of organic and functional neurotoxic disorders at early stages of preclinical studies.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88443040","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 : 2020-09-18DOI: 10.30895/1991-2919-2020-10-3-201-210
D. P. Romodanovsky
In order to be registered, generic drugs with a narrow therapeutic range have to undergo bioequivalence or therapeutic equivalence studies. In most cases, comparative pharmacokinetic studies and demonstration of bioequivalence between the test and the reference products are sufficient for this group of drugs. However, there is no established official definition in Russia for the group of drugs that are regarded as having a narrow therapeutic range. Evaluation of bioequivalence of such drugs has to be performed providing for narrower confidence intervals, which entails certain problems at the stage of bioequivalence study planning. Finding solutions to the problems stated above is of great importance. The aim of the study was to develop approaches to planning bioequivalence studies of drugs with a narrow therapeutic range. Materials and methods: the paper analyses the results of 33 bioequivalence studies of drugs with a narrow therapeutic range, in which Cmax, AUC0-t, and tmax were calculated. Intra-individual variation and weighted mean intra-individual variation of Cmax and AUC0-t were estimated in the study. Statistical processing was performed using IBM SSPS Statistics v.25. and Microsoft Office Excel 2016. Results: the paper summarises criteria for categorising drugs as having a narrow therapeutic range and describes general requirements for assessing their bioequivalence. A number of bioequivalence studies of generic valproic acid, carbamazepine, levothyroxine, tacrolimus, and cyclosporine products which meet the criteria for drugs with a narrow therapeutic range, were analysed retrospectively. The data on their pharmacokinetics and intra-individual variation were calculated. It also summarises requirements for bioequivalence evaluation of drugs with a narrow therapeutic range. The paper gives product-specific recommendations for performing bioequivalence studies. Conclusion: the study helped to formulate approaches to the planning of bioequivalence studies of generic drugs with a narrow therapeutic range using the examples of valproic acid, carbamazepine, levothyroxine, tacrolimus, and cyclosporine.
{"title":"Relevant Issues of Planning Bioequivalence Studies of Drugs with a Narrow Therapeutic Range","authors":"D. P. Romodanovsky","doi":"10.30895/1991-2919-2020-10-3-201-210","DOIUrl":"https://doi.org/10.30895/1991-2919-2020-10-3-201-210","url":null,"abstract":"In order to be registered, generic drugs with a narrow therapeutic range have to undergo bioequivalence or therapeutic equivalence studies. In most cases, comparative pharmacokinetic studies and demonstration of bioequivalence between the test and the reference products are sufficient for this group of drugs. However, there is no established official definition in Russia for the group of drugs that are regarded as having a narrow therapeutic range. Evaluation of bioequivalence of such drugs has to be performed providing for narrower confidence intervals, which entails certain problems at the stage of bioequivalence study planning. Finding solutions to the problems stated above is of great importance. The aim of the study was to develop approaches to planning bioequivalence studies of drugs with a narrow therapeutic range. Materials and methods: the paper analyses the results of 33 bioequivalence studies of drugs with a narrow therapeutic range, in which Cmax, AUC0-t, and tmax were calculated. Intra-individual variation and weighted mean intra-individual variation of Cmax and AUC0-t were estimated in the study. Statistical processing was performed using IBM SSPS Statistics v.25. and Microsoft Office Excel 2016. Results: the paper summarises criteria for categorising drugs as having a narrow therapeutic range and describes general requirements for assessing their bioequivalence. A number of bioequivalence studies of generic valproic acid, carbamazepine, levothyroxine, tacrolimus, and cyclosporine products which meet the criteria for drugs with a narrow therapeutic range, were analysed retrospectively. The data on their pharmacokinetics and intra-individual variation were calculated. It also summarises requirements for bioequivalence evaluation of drugs with a narrow therapeutic range. The paper gives product-specific recommendations for performing bioequivalence studies. Conclusion: the study helped to formulate approaches to the planning of bioequivalence studies of generic drugs with a narrow therapeutic range using the examples of valproic acid, carbamazepine, levothyroxine, tacrolimus, and cyclosporine.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72718649","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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