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Scientist relevance. Antibacterials can have nephrotoxic effects because medicinal products of this class are primarily excreted by the kidneys.Aim. The study aimed to analyse literature data on the mechanisms, risk factors and specific features of toxic nephropathy development during antibiotic therapy.Discussion. The article considers mechanisms of development of acute interstitial nephritis, acute tubular necrosis, crystal deposits in the tubules, proximal or distal tubulopathy with electrolyte abnormalities during the use of antibiotics. Nephrotoxicity was shown to be most often associated with the use of aminoglycosides, beta-lactams, and vancomycin. The authors analysed the dependence of nephrotoxicity on antibacterial agent lipophilicity and drug–drug interactions. The main risk factors for developing nephropathy are older age; male sex; black race; hypovolaemia; arterial hypotension; angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, non-steroidal anti-inflammatory drugs or their combinations; and individual genetic characteristics. Nephrotoxicity is associated with genetic characteristics of the systems responsible for metabolism and excretion of antibacterial products: cytochrome P450 isoenzymes, P-glycoprotein, multidrug resistance protein (MRP), multidrug and toxin extrusion (MATE), breast cancer resistance protein (BCRP), and organic anion transporters. Severe generalised infections change pharmacokinetic parameters of antibacterial products. This should be taken into account when prescribing the hydrophilic antibiotics that are excreted by tubular secretion and reabsorbed in the renal tubules.Conclusions. The study demonstrated the effectiveness of the method comprising a combination of dose adjustment based on therapeutic drug monitoring results and renal function monitoring for improving the safety of antibiotic therapy.

The relationship between dissolution and bioavailability is an example of the interdependency between the quality of a medicinal product and its safety and efficacy. The uniqueness of thioctic acid is that it can exist in an oxidised and a reduced form, showing lipophilic (lipoic acid) and hydrophilic (dihydrolipoic acid) properties. Bioavailability studies of thioctic acid are necessary to evaluate the expected therapeutic effect and mitigate side effects of the medicinal product.The aim of the study was to carry out equivalence dissolution testing to compare the release of thioctic acid from medicinal products produced by several manufacturers.Materials and methods: the study used a reference medicinal product and three multisource medicinal products by different manufacturers; more specifically, film-coated tablets containing 600 mg of thioctic acid. The experiment was carried out in dissolution media at pH of 6.8±0.05 and 1.2±0.05. Statistical analysis was performed by calculating the average amounts of the substance dissolved, the standard deviation (SD), and the relative standard deviation (RSD, %) using Microsoft Office Excel 2007.Results: The authors chose the testing conditions (dissolution media pH values of 6.8±0.05 and 1.2±0.05) taking into account the nature and characteristics of thioctic acid. The comparison of thioctic acid release profiles based on the calculation of the similarity factor (f2) showed that the dissolution profiles of multisource medicinal products 2 and 3 at pH 6.8 were equivalent to that of the reference medicinal product (more than 85% of the active pharmaceutical ingredient released within 15 minutes) and the dissolution profile of multisource medicinal product 1 was not equivalent to it (with f2 of 28).Conclusions: the established differences in the rate and degree of active ingredient release from the studied medicinal products may indicate possible differences in their pharmacological effectiveness in vivo.

Rational use of glybenclamide products in the treatment of patients with type 2 diabetes remains a high-priority task. The paper offers a summary of the main groups of glibenclamide drugs and describes pharmacogenetics of glybenclamide. Glibenclamide is metabolized by the enzyme cytochrome P450 2C9 (CYP2C9). Individuals with genetically determined low CYP2C9 activity are at an increased risk of hypoglycaemia. Carriers of CYP2C9*3 and CYP2C9*2 alleles tend to have higher concentrations of glybenclamide in blood and increased insulin secretion. Pharmacogenetic testing of patients and drug concentration monitoring using HPLC-MS can help reduce the risk of hypoglycemia during glibenclamide treatment. Based on literature review the authors selected the method characterised by a simple sample preparation procedure, short analysis time, and a wide analytical range for the substances being determined. This method can be useful both for bioequivalence studies and evaluation of glibenclamide products interchangeability. Glibenclamide pharmacokinetics is characterised by high interindividual variability. This may lead to both an increased risk of hypoglycemia and drug inefficacy, therefore, when prescribing glibenclamide, a physician should carefully control the efficacy and safety of drug therapy.

This article looks into interchangeability and therapeutic equivalence of innovator and generic anticonvulsants — the first-generation and new antiepileptic drugs (AEDs). The results of a number of clinical trials assessing therapeutic equivalence of generic AEDs support the opinion that these medicines could only be substituted provided an ultra-cautious approach is used, even if the case involves only one International Nonproprietary Name, including, but not limited to different dosage forms of one and the same product. The aim of the study was to analyse factors leading to incorrect assessment of therapeutic equivalence of new and generic anticonvulsant drugs, and to improve methodological approaches to conducting clinical trials of these products. The paper cites data from Russian and foreign sources which state that the substitution of AEDs in some patients in full remission may result in adverse reactions or relapse of seizures. The analysis of the experience of scientific, expert, and regulatory institutions made it possible to develop a course of actions to be used when substituting AEDs and conducting clinical trials that assess therapeutic equivalence of new and generic anticonvulsants. The proposed methodology will help minimise potential health risks brought about by various factors that result in incorrect assessment of AEDs therapeutic equivalence and interchangeability.

The article analyses the problem of interchangeability of glibenclamide-containing drugs that sometimes lack therapeutic equivalence even though their bioequivalence has been proven. The authors formulated the key factors affecting interchangeability of glibenclamide drugs and highlighted conditions that compromise interchangeability. Special attention was given to clinical pharmacology of glibenclamide and adverse reactions associated with sulfonylurea products. The article offers a summary of the main groups of glibenclamide drugs. It also substantiates the need for better coordination of production and clinical use of glibenclamide drugs which will help to ensure the comparability of generic and reference glibenclamide drugs in the long run.

The article analyses scientific literature on the use of pharmacogenetic testing to optimize sulfonylurea treatment of patients with type 2 diabetes. It describes characteristics of modern sulfonylurea drugs used in the treatment of type 2 diabetes, including their mode of action, and the frequency of associated hypoglycaemia events. The authors analysed the main pharmacokinetic parameters of sulfonylureas (bioavailability, protein binding, metabolites, elimination, etc.), and adverse reactions associated with these drugs. Based on integrated data on Cytochrome P450 isoenzymes role in sulfonylureas metabolism, and determination of the role played by polymorphism of the gene encoding this fragment, the authors demonstrated the usefulness of pharmacogenetic testing combined with phenotypic (losartan) testing in the treatment of patients with type 2 diabetes.

The article reviews scientific literature and regulatory documents on safe and efficacious use of levothyroxine medicines. Levothyroxine has less than a twofold difference between the minimal toxic concentration and minimal effective concentration. The article discusses the issue of switching between levothyroxine medicines that can be therapeutically nonequivalent while having proven bioequivalence. The article reviews results of levothyroxine medicines interchangeability studies in different countries. The authors assert the need for improving the coordination of manufacturing and the clinical use of levothyroxine medicines, which will help achieve the equivalence of generic and innovator medicines in the future.

The article presents a review of modern regulatory and legal framework and draft regulatory documents on circulation of interchangeable drugs with regard to standard instructions for medical use. The analysis included more than 70 documents. There are two slightly different notions in this field: a generic drug and an interchangeable drug. A generic drug is not necessarily an interchangeable drug. The interchangeability of a drug is determined during pre-marketing evaluation. Some differences concerning normative requirements to the content of standard instructions for interchangeable drugs have been observed when comparing the regulatory framework of Russia, CIS countries and the EU. It is necessary to look not only at bioequivalence as an equivalent of interchangeability, but also take into account characteristics of excipients, and therapeutic equivalence based on preclinical and clinical trial results. The analysis of differences in regulatory documents can form the basis for further harmonization of requirements to instructions for medical use of interchangeable drugs.