The review compares individual case safety reports (ICSRs) for hydroxychloroquine, favipiravir, and the lopinavir/ ritonavir combination registered in the VigiBase global database during 6 months in 2019 and the same period in 2020 which coincides with the global “first wave”. The aim of the study was to identify specific aspects of using these drugs for the treatment of COVID-19. There was an increase in the use of hydroxychloroquine, favipiravir, and the lopinavir/ritonavir combination during the pandemic, which was accompanied by a significant deterioration in the quantitative and qualitative safety profiles of these drugs. The review summarises the main risks of using these drugs for COVID-19 treatment and highlights the need for revision of the recommendations for their use in the context of the new coronavirus disease.

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.

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.

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 K_i and/or half maximal inhibitory concentration IC₅₀ for predicting DDI. One of the main problems is the variability of K_i and IC₅₀ values between laboratories, which requires the development of general recommendations for different transporters as regards methods of determination of these parameters.

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.

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 technique 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 × 150 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. Pharmacokinetic 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-desmethyl 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.

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 C_max, AUC_0-t, and t_max were calculated. Intra-individual variation and weighted mean intra-individual variation of C_max and AUC_0-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.

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/10.30895/1991-2919-2020-10-2-82-88

Dear 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”.