Polymorphism: the influence on the quality of drugs and actual methods of analysis

Polymorphism is a phenomenon of existence of an individual substance in states with different crystalline structure, each of these states is called a polymorphic modification (PM). The possibility of developing new drugs by detecting the biological activity of xenobiotics is considered to be largely exhausted, so recently, along with the search and development of new drugs, the task of improving known drugs, in particular, through the use of medicinal substances (MS) based on a certain PM of the active substance. Such technologies allow improving the properties, ensuring the quality and safety of drugs at a higher level, and also reducing the costs of developing patent-protected drugs, which contributes to the development of the pharmaceutical industry

Актуальные изменения в системе фармаконадзора в России и ЕАЭС

The Eurasian Economic Union (EAEU) is an international organization for regional economic integration, established by the Treaty on the Eurasian Economic Union, which currently includes 5 countries - Russia, Kazakhstan, Belarus, Armenia and Kyrgyzstan. The EAEU ensures the freedom of goods movement, as well as services, capital and labor, conducting a coordinated, agreed/unified economic policy. The current practice of pharmacovigilance in the EAEU is of interest to potential foreign investors and market players.The aim of this study was to analyze the recent changes in pharmacovigilance in the EAEU countries in order to adopt the strategy of the pharmaceutical industry players.Materials and methods. The regulatory base of pharmacovigilance in the EAEU countries and the unified EAEU provisions on adverse reactions (ADR) were analyzed. A critical analysis of the current periodic safety update reports (PSUR) and risk management plans (RMP) was also carried out.Results. The united EAEU drug market is a complex system that incorporates 35 regulations, including the variety of good practice guidelines regarding the circulation of medicinal products (GMP, GCP, GLP, GDP, and GVP). This group of regulations contains basic documents on the inspection of production lines, the assessment of generic equivalence, the development of biological drugs, and the pharmacovigilance (PV). Currently, the ADR reporting in the EAEU countries is at a level lower than that in Russia. The common EAEU database of identified ADRs has been already initiated, but the number of incoming signals is quite small. The most common flaws of the PSUR are the late reports, the incorrect format and contents of those; the inconsistent information about the product, different from that of Roszdravnadzor, the discrepancy between the Patients information leaflet (“Instruction for medical use”) and the Summary of Product Characteristics (SmPC), and the lack of important and relevant scientific and clinical information. In the EAEU, the submission of Risk Management Plan (RMP) as part of the registration dossier is required for any new medication (New Chemical Entity), including a new combination of drugs. The present article also covers other updates in the Pharmacovigilance system, regulated by the Good Pharmacovigilance practice, which entered into effect on 01.01.2017, as well as the updated tasks for harmonization within the EAEU.Conclusions. The medicinal products circulating in the EAEU have to be checked for their efficacy and safety in order to identify possible negative consequences and/or individual patient intolerance. This information will serve to warn the medical staff and patients, veterinary specialists and animal owners about potential hazards of using these products. In the near future, the Eurasian Union plans to launch a “sanitation” campaign in the pharmaceutical market and get rid of low-effective and unsafe drugs. In this respect, the issues of pharmacovigilance become particularly relevant.Евразийский экономический союз (ЕАЭС) - международная организация региональной экономической интеграции, учрежденная Договором о Евразийском экономическом союзе, в которую на текущий момент входят пять стран - Россия, Казахстан, Белоруссия, Армения и Киргизия. В ЕАЭС обеспечивается свобода движения товаров, а также услуг, капитала и рабочей силы, проведение скоординированной, согласованной или единой политики в отраслях экономики. Прежде всего для иностранных игроков рынка представляет интерес анализ существующей практики фармаконадзора, что определяет цель данной работы.Цель - анализ изменений в системе фармаконадзора в России и ЕАЭС для адаптации стратегии игроков фармацевтической индустрии.Материалы и методы. Проанализирована нормативная база фармаконадзора в странах, входящих в ЕАЭС, единая база ЕАЭС по нежелательным реакциям (НР). Проведен критический анализ сложившейся практики периодических отчетов по безопасности лекарственного средства (ПООБ), планов управления рисками (ПУР).Результаты. Общий лекарственный рынок ЕАЭС представляет собой сложную систему из 35 нормативных актов, которые включают надлежащие практики по обращению лекарственных средств (GMP, GCP, GLP, GDP, GVP). Эти нормативные документы определяют порядок инспектирования производств, подтверждение эквивалентности воспроизведенных лекарств, разработку биологических лекарственных препаратов и фармаконадзор (ФН). В странах ЕАЭС репортирование НР находится на более низком уровне, чем в России. Единая информационная база ЕАЭС данных по выявленным НР на ЛС уже начала свою работу, но количество поступивших в нее сигналов пока незначительно. Наиболее частые ошибки в ПООБ: несоответствие сроков; формы; содержания разделов; отличия информации об ЛС от таковой, полученной Росздравнадзором; отличия информации в инструкции по медицинскому применению от таковой в документе «Справочная информация по безопасности»; отсутствие важной и актуальной информации научно-клинического характера. Подача ПУР необходима в составе регистрационного досье на любой ранее незарегистрированный в ЕАЭС лекарственный препарат, в т. ч. ранее незарегистрированной комбинации. В работе приведены также другие нововведения в системе ФН, регламентированные Правилами надлежащей практики ФН, вступившими в силу 01.01.2017 г., а также актуальные задачи для гармонизации в рамках ЕАЭС на ближайшую перспективу.Заключение. Все находящиеся в обращении в ЕАЭС лекарственные препараты должны подвергаться мониторингу эффективности и безопасности для выявления возможных нежелательных последствий их применения, индивидуальной непереносимости, предупреждения медицинских работников и пациентов, а также их защиты от применения подобных лекарственных препаратов. В ближайшее время ожидается «санация» фармацевтического рынка, с которого исчезнут препараты, не подтвердившие свою эффективность, а также препараты с неблагоприятным профилем безопасности, в связи с чем вопросы, связанные с ФН, имеют особую актуальность

Single-Dose Bioequivalence Study of Rivaroxaban-Containing Medicinal Products in Healthy Volunteers

Therapeutically, new oral anticoagulants (NOACs) are considered to be non-inferior or superior to vitamin K antagonists (warfarin). NOACs are included in current guidelines for the treatment of various cardiovascular diseases. Rivaroxaban medicinal products have been shown to effectively fight thrombotic complications of the new coronavirus infection, COVID-19. The wide clinical use of rivaroxaban products motivates the development of generics.The aim of the study was to compare the pharmacokinetics and safety of rivaroxaban medicinal products in a single-dose bioequivalence study in healthy volunteers under fasting conditions.Materials and methods: the bioequivalence study compared single-dose oral administration of Rivaroxaban, 10 mg film-coated tablets (NovaMedica Innotech LLC, Russia), and the reference product Xarelto®, 10 mg filmcoated tablets (Bayer AG, Germany), in healthy volunteers under fasting conditions. The open, randomised, crossover trial included 46 healthy volunteers. Each of the medicinal products (the test product and the reference product) was administered once; blood samples were collected during the 48 h after the administration. The washout between the study periods lasted 7 days. Rivaroxaban was quantified in plasma samples of the volunteers by high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS).Results: no adverse events or serious adverse events were reported for the test and reference products during the study. The following pharmacokinetic parameters were obtained for Rivaroxaban and Xarelto®, respectively: Cmax of 134.6 ± 58.0 ng/mL and 139.9 ± 49.3 ng/mL, AUC0–48 of 949.7 ± 354.5 ng×h/mL and 967.6 ± 319.9 ng×h/mL, AUC 0–∞ of 986.9 ± 379.7 ng×h/mL and 1003.6 ± 320.4 ng×h/mL, T1/2 of 8.2 ± 3.2 h and 7.8 ± 3.3 h. The 90% confidence intervals for the ratios of Cmax, AUC0–48, and AUC0–∞ geometric means were 88.04–108.67%, 89.42–104.92% and 89.44–104.81%, respectively.Conclusions: the test product Rivaroxaban and the reference product Xarelto® were found to have similar rivaroxaban pharmacokinetics and safety profiles. The study demonstrated bioequivalence of the medicinal products

Обзор существующих методик оценки активности CYP2D6 с применением экзогенных и эндогенных маркеров

Peculiarities of functioning and polymorphism of cytochrome P450 isoenzyme CYP2D6. Existing methods for determining its activity using endogenous markers. A review of studies on the screening of endogenous substrates, biotransformation mainly under the influence of isoenzyme CYP2D6. The results by determination pinoline relationship to its metabolite 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline in vitro in cell culture and in vivo in mice for evaluation isoenzyme activity CYP2D6.Приведены особенности функционирования и полиморфизма изофермента цитохрома Р450 CYP2D6. Рассмотрены существующие методики определения его активности при помощи эндогенных маркеров. Представлен обзор исследований по скринингу эндогенных субстратов, подвергающихся биотрансформации преимущественно под воздействием изофермента CYP2D6. Изложены результаты по определению отношения пинолина к его метаболиту 6-гидрокси-1,2,3,4-тетрагидро-бета-карболину in vitro на культуре клеток и in vivo на мышах для последующей оценки активности изофермента CYP2D6

ЭФФЕКТИВНОСТЬ И БЕЗОПАСНОСТЬ ЛЕКАРСТВЕННЫХ ФОРМ МОРФИНА ГИДРОХЛОРИДА У ОНКОЛОГИЧЕСКИХ ПАЦИЕНТОВ С ХРОНИЧЕСКИМ БОЛЕВЫМ СИНДРОМОМ

Purpose of the study: to assess the efficacy and safety of morphine hydrochloride in the form of 10 mg filmcoated tablets and 1 % solution for injection in cancer patients with chronic pain syndrome of strong intensity.Material and Methods. The study included 110 cancer patients with chronic pain syndrome of strong intensity. The study was conducted in compliance with the principles of the Helsinki Declaration, ICH GCP, GOST R 52379-2005, as well as other Russian laws regulating the conduct of clinical trials and work with opioid analgesics. Patients were randomized at a 1:1 ratio. Group I received 10 mg film-coated morphine tablets, 1 tablet orally every 4 hours for 7 days. Group II received 1 % morphine solution for injection, intramuscularly, 4 mg every 4 hours for 7 days. A Numeric Rating Scale for Pain (NRS, 0–100 mm) was used to assess the level of pain. The safety assessment was based on the collection of data on the registration of adverse events, including opioid-associated adverse effects.Results. Enteral and parenteral morphine administration for 7 days demonstrated a statistically significant decrease in the intensity of pain syndrome in cancer patients. The use of morphine hydrochloride in tablets reduced the number of additional analgesics prescribed for cancer patients. Regarding opioid-associated adverse effects, a statistically significant difference in the incidence of constipation between two groups was observed.Conclusion. The study showed that tablets and injectable dosage forms of morphine hydrochloride were comparable in efficacy and safety profile, thus predetermining the widespread clinical use of drugs produced by the domestic manufacturer in accordance with the “pain relief ladder”, proposed by WHO. Цель исследования – провести сравнительную оценку эффективности и безопасности морфина гидрохлорида в форме таблеток 10 мг, покрытых пленочной оболочкой, и 1 % раствора для инъекций у онкологических пациентов с хроническим болевым синдромом сильной интенсивности.Материал и методы. В исследование было включено 110 онкологических больных с хроническим болевым синдромом сильной интенсивности на базе 6 региональных исследовательских центров, охватывающих территорию Сибирского и Центрального федерального округов. Процедура проведения исследования соответствовала принципам Хельсинкской декларации, ICH GCP, ГОСТ Р 52379-2005, а также российским законам, регламентирующим проведение клинических исследований и работу с НЛП. Пациенты были рандомизированы в соотношении 1:1. Группа I получала таблетки морфина 10 мг, покрытые пленочной оболочкой, по 1 таблетке перорально каждые 4 ч в течение 7 дней. Группа II получала раствор морфина для инъекций 1 % внутримышечно по 4 мг каждые 4 ч на протяжении 7 дней. Для оценки уровня боли использовали общепринятую 100 мм цифровую рейтинговую шкалу оценки боли (NRS). Оценка безопасности лечения проводилась на основании сбора данных о регистрации нежелательных явлений, в том числе опиоид-ассоциированных.Результаты. Энтеральная и парентеральные формы отечественного морфина продемонстрировали статистически значимое снижение интенсивности болевого синдрома на фоне 7-дневной терапии. Применение таблетированной формы морфина гидрохлорида способствует снижению числа назначений дополнительных анальгетиков у онкологических больных. Безопасность лекарственных форм морфина гидрохлорида в целом была сопоставима, обращает на себя внимание при оценке опиоид-ассоциированных нежелательных явлений статистически значимая разница между сравниваемыми группами по частоте запоров.Заключение. В проведенном исследовании было показано, что таблетированная и инъекционная лекарственные формы препаратов морфина гидрохлорида сопоставимы по эффективности и профилю безопасности, что может предопределять широкое клиническое применение препаратов отечественного производителя, согласно принципам терапии «Лестница обезболивания ВОЗ».

Влияние изофермента CYP2D6 на метаболизм лекарственных препаратов и методы определения его активности

The article presents relevant information on the features of cytochrome P450 isoenzyme CYP2D6 functioning. 20-25% of drugs are metabolized by the action of CYP2D6. Determination of its activity allows for adjusting pharmacotherapy to increase the efficacy and safety of a drug or a combination of drugs. Cytochrome P450 isoenzymes genotyping and phenotyping methods allow for choosing the dosage and dosing regimen for patients on an individual basis. This article describes the genetic characteristics affecting CYP2D6. CYP2D6 polymorphism has a significant impact on pharmacokinetics and metabolism of a drug. This may lead to side effects, or decrease the pharmacological action of the drug. The article covers the cases of change in clinical response to receiving β-blockers (metoprolol), antidepressants (venlafaxine) and opioids (codeine). These changes occurred in the presence of certain CYP2D6 alleles which speed up or slow down the metabolism. It also provides information on drug-drug interactions involving inhibition of cytochrome P450 isoenzyme CYP2D6. Genotyping methods are used to determine the potential activity of CYP2D6. Dose adjustment is carried out basing on the results obtained. The current isoenzyme status is defined by phenotyping methods. CYP2D6 activity can be evaluated by determining the ratio of the substrate and its metabolite using HPLC. Pinoline, which is metabolized to 6-hydroxy-1,2,3,4-tetrahydro-β-carboline, is the endogenous substrate for estimating the activity of CYP2D6.В статье приведена актуальная информация об особенностях функционирования изофермента цитохрома Р450 CYP2D6. Метаболизм 20-25% лекарственных препаратов происходит под действием изофермента CYP2D6. Определение его активности позволяет скорректировать фармакотерапию с увеличением эффективности и безопасности препарата или комбинации препаратов. Методы генотипирования и фенотипирования изоферментов цитохрома Р450 позволяют индивидуально для пациента подбирать дозировку, режим дозирования. В статье описаны генетические особенности, которые оказывают воздействие на изофермент CYP2D6. Полиморфизм изофермента CYP2D6 оказывает существенное влияние на метаболизм и фармакокинетику лекарственного препарата, что может привести кпобочным эффектом или снижению фармакологического действия препарата. Рассмотрены случаи изменения клинического ответа на прием β-блокаторов (метопролол), антидепрессантов (венфлаксин) и опиоидов (кодеин). Данные изменения происходили при наличии определенных аллелей CYP2D6, которые ускоряют или замедляют метаболизм. Также представлена информация о межлекарственном взаимодействиях, при которых происходит ингибирование изофермента цитохрома Р450 CYP2D6. Для определения потенциальной активности изофермента CYP2D6 используются методы генотипирования. На основании полученных результатов, проводится корректировка дозы. Текущий статус изофермента определяется методами фенотипирования. Определение соотношения субстрата и его метаболита методом высокоэффективной жидкостной хроматографии позволяют произвести оценку активности изофермента. Эндогенным субстратом для определения активности изофермента CYP2D6 является пинолин, метаболитом которого является 6-гидрокси-1,2,3,4-тетрагидро-β-карболин

Recent changes in the pharmacovigilance system in the Russian Federation and the EAEU

The Eurasian Economic Union (EAEU) is an international organization for regional economic integration, established by the Treaty on the Eurasian Economic Union, which currently includes 5 countries - Russia, Kazakhstan, Belarus, Armenia and Kyrgyzstan. The EAEU ensures the freedom of goods movement, as well as services, capital and labor, conducting a coordinated, agreed/unified economic policy. The current practice of pharmacovigilance in the EAEU is of interest to potential foreign investors and market players.The aim of this study was to analyze the recent changes in pharmacovigilance in the EAEU countries in order to adopt the strategy of the pharmaceutical industry players.Materials and methods. The regulatory base of pharmacovigilance in the EAEU countries and the unified EAEU provisions on adverse reactions (ADR) were analyzed. A critical analysis of the current periodic safety update reports (PSUR) and risk management plans (RMP) was also carried out.Results. The united EAEU drug market is a complex system that incorporates 35 regulations, including the variety of good practice guidelines regarding the circulation of medicinal products (GMP, GCP, GLP, GDP, and GVP). This group of regulations contains basic documents on the inspection of production lines, the assessment of generic equivalence, the development of biological drugs, and the pharmacovigilance (PV). Currently, the ADR reporting in the EAEU countries is at a level lower than that in Russia. The common EAEU database of identified ADRs has been already initiated, but the number of incoming signals is quite small. The most common flaws of the PSUR are the late reports, the incorrect format and contents of those; the inconsistent information about the product, different from that of Roszdravnadzor, the discrepancy between the Patients information leaflet (“Instruction for medical use”) and the Summary of Product Characteristics (SmPC), and the lack of important and relevant scientific and clinical information. In the EAEU, the submission of Risk Management Plan (RMP) as part of the registration dossier is required for any new medication (New Chemical Entity), including a new combination of drugs. The present article also covers other updates in the Pharmacovigilance system, regulated by the Good Pharmacovigilance practice, which entered into effect on 01.01.2017, as well as the updated tasks for harmonization within the EAEU.Conclusions. The medicinal products circulating in the EAEU have to be checked for their efficacy and safety in order to identify possible negative consequences and/or individual patient intolerance. This information will serve to warn the medical staff and patients, veterinary specialists and animal owners about potential hazards of using these products. In the near future, the Eurasian Union plans to launch a “sanitation” campaign in the pharmaceutical market and get rid of low-effective and unsafe drugs. In this respect, the issues of pharmacovigilance become particularly relevant

Assessing the impact of the automation on the variability of the «Dissolution» test results as exemplified by «Betahistine hydrochloride tablets 16 mg»

The article analyses the results of dissolution testing of Betahistine hydrochloride 16 mg tablets using both manual and automatic sampling. The analysis showed that the data obtained with manual sampling are statistically identical to those obtained with automatic sampling in terms of average values and variance (with significance level α = 0,05), which confirms that the automation of the dissolution test does not affect the variability of test results

EFFICACY AND SAFETY OF MORPHINE HYDROCHLORIDE IN CANCER PATIENTS WITH CHRONIC PAIN

Purpose of the study: to assess the efficacy and safety of morphine hydrochloride in the form of 10 mg filmcoated tablets and 1 % solution for injection in cancer patients with chronic pain syndrome of strong intensity.Material and Methods. The study included 110 cancer patients with chronic pain syndrome of strong intensity. The study was conducted in compliance with the principles of the Helsinki Declaration, ICH GCP, GOST R 52379-2005, as well as other Russian laws regulating the conduct of clinical trials and work with opioid analgesics. Patients were randomized at a 1:1 ratio. Group I received 10 mg film-coated morphine tablets, 1 tablet orally every 4 hours for 7 days. Group II received 1 % morphine solution for injection, intramuscularly, 4 mg every 4 hours for 7 days. A Numeric Rating Scale for Pain (NRS, 0–100 mm) was used to assess the level of pain. The safety assessment was based on the collection of data on the registration of adverse events, including opioid-associated adverse effects.Results. Enteral and parenteral morphine administration for 7 days demonstrated a statistically significant decrease in the intensity of pain syndrome in cancer patients. The use of morphine hydrochloride in tablets reduced the number of additional analgesics prescribed for cancer patients. Regarding opioid-associated adverse effects, a statistically significant difference in the incidence of constipation between two groups was observed.Conclusion. The study showed that tablets and injectable dosage forms of morphine hydrochloride were comparable in efficacy and safety profile, thus predetermining the widespread clinical use of drugs produced by the domestic manufacturer in accordance with the “pain relief ladder”, proposed by WHO

Influence of CYP2d6 on drug metabolism and methods for determining its activity

The article presents relevant information on the features of cytochrome P450 isoenzyme CYP2D6 functioning. 20-25% of drugs are metabolized by the action of CYP2D6. Determination of its activity allows for adjusting pharmacotherapy to increase the efficacy and safety of a drug or a combination of drugs. Cytochrome P450 isoenzymes genotyping and phenotyping methods allow for choosing the dosage and dosing regimen for patients on an individual basis. This article describes the genetic characteristics affecting CYP2D6. CYP2D6 polymorphism has a significant impact on pharmacokinetics and metabolism of a drug. This may lead to side effects, or decrease the pharmacological action of the drug. The article covers the cases of change in clinical response to receiving β-blockers (metoprolol), antidepressants (venlafaxine) and opioids (codeine). These changes occurred in the presence of certain CYP2D6 alleles which speed up or slow down the metabolism. It also provides information on drug-drug interactions involving inhibition of cytochrome P450 isoenzyme CYP2D6. Genotyping methods are used to determine the potential activity of CYP2D6. Dose adjustment is carried out basing on the results obtained. The current isoenzyme status is defined by phenotyping methods. CYP2D6 activity can be evaluated by determining the ratio of the substrate and its metabolite using HPLC. Pinoline, which is metabolized to 6-hydroxy-1,2,3,4-tetrahydro-β-carboline, is the endogenous substrate for estimating the activity of CYP2D6