Introduction  

Fungal diseases (mycoses) are an important medical and social problem of modern society [1, 2]. In addition to superficial mycoses, when the lesion in most cases affects the nail plates, systemic mycoses that affect vital organs and systems are becoming more widespread. Every year, more than 1.5 million people become victims of fungal diseases. According to the latest global estimates, 3000000 cases of chronic pulmonary aspergillosis, 223100 cases of cryptococcal meningitis, 700000 cases of invasive candidiasis ending in severe candida sepsis are registered annually. No less severe mycotic infections, such as pneumocystis pneumonia, affect about 500,000 people annually, invasive aspergillosis and disseminated histoplasmosis-250,000 and 3100,000 people, respectively [3, 4]. The average annual incidence of lethal mycotic infections in the Russian Federation is 11,840 cases of candidiasis, 3,238 cases of invasive aspergillosis, and 52,311 cases of chronic lung aspergillosis [5].

Various factors contribute to such a rapid spread of mycoses. So, some surface infections are quite trivial, for example, mycosis of the feet and hands, however, invasive systemic mycoses occur in patients with immunodeficiency conditions caused by the use of glucocorticoids, antitumor, and immunosuppressive drugs. Immunodeficiency conditions also occur in the presence of HIV infection and after transplantation of internal organs and tissues. In addition, the number of patients with tuberculosis has recently increased, which is also a significant risk factor for fungal infection [6-8].

Currently, the pharmaceutical market is rich in various medicines, which are both mono- and multicomponent, and recently combined. The search for new pharmacologically active molecules with antifungal activity is carried out, which is associated with the optimization of the general profile of patients (age group, pregnancy), with a decrease in toxicity (especially for systemic antimycotics), as well as the spectrum of antifungal action [9-11]. Among modern antifungal drugs, an important place is occupied by azoles, which have been used since the second half of the 20th century [10]. This group includes imidazoles and triazoles, the mechanism of action of which is to inhibit the enzyme 14-alpha-sterol demethylase, which leads to a violation of the construction of the cell wall of fungi [12]. However, better tolerability and less serious side effects should be noted in representatives of triazoles used in the treatment of systemic mycoses (Fungal meningitis, cryptococcosis, systemic candidiasis, aspergillosis) [10, 13]. There are 2-generation triazoles, among which we can distinguish relatively new voriconazole, structurally similar to fluconazole, but with a wider spectrum of action, including against fungi resistant to fluconazole [14]. Among the newer representatives of the 2nd generation, isavuconazole can be distinguished, under the spectrum of action of which yeast (genera Candida, Cryptococcus, etc.), mycelial fungi (genera Aspergillus, including strains resistant to amphotericin B and even to echinocandins), dimorphic fungi (Histoplasma capsulatum, Coccidiodes spp., Blastomyces dermatitidis) fall [15, 16]. Clinical trials have also shown that isavuconazole is not inferior to voriconazole in invasive aspergillosis, alternative therapy for the emergency treatment of mucormycosis, and is suitable for the treatment of invasive candidiasis [14, 17].

Due to the wide distribution and introduction of new triazole derivatives into clinical practice, it is important to study the range of this group in the modern Russian pharmaceutical market. In this research, we used the marketing methods of analysis – ABC and XYZ, with the further creation of an integrated matrix that allows us to get an idea of the place of each drug of the analyzed group in the assortment of pharmaceutical organizations, their contribution to the turnover and an idea of the structure of the use of these antifungal drugs. Such a matrix will help to adjust the existing modern range of antifungal medicines for pharmaceutical organizations.

Materials and Methods

Materials

The Russian pharmaceutical market of antifungal medicines are represented by 1432 drugs.

Methods: ABC analysis, XYZ analysis, statistical analysis, comparative analysis, content analysis, graphical method.

In this article, we studied the annual reports of analytical agencies for the research of the Russian pharmaceutical market of antifungal drugs for 2019. Based on these data, the drugs were grouped according to the chemical structure of the active substances, where the most widely represented group on the Russian pharmaceutical market was identified. Then ABC - and XYZ-analyses of this group were carried out with further construction of the integrated ABC-XYZ matrix.

ABC analysis is a method of resource research, which consists of dividing the assortment of products into categories A, B, and C, which make up 80, 10, and 10% of the sales structure (in physical and price terms), respectively. This principle is called the Pareto principle, according to which 20% of the effort provides 80% of the result. As a result, each category formed by the ABC method has its characteristics: category A includes the most valuable goods for the organization that provides maximum sales and are constantly in the assortment, category B includes goods that provide a stable volume of sales for the organization, category C includes goods that make the least contribution to assortment sales, since they practically do not bring income [18, 19]. Thus, it is possible to identify the most valuable products for the retail segment of the pharmaceutical market, identify representatives who are "outsiders" in the commercial assortment of the studied group of medicines, as well as identify drugs that form the inventory of pharmaceutical organizations. During the ABC analysis, the trade names assigned to each drug by the manufacturers were used (without taking into account the different dosage forms, the specific brand of the manufacturer was taken into account). Based on the calculation of the total sales amount for 2019 (taking into account all quarters) (wholesale price in rubles), antifungal medicines were sorted in descending order, followed by the division of each specific commercial drug into groups A, B, and C based on the calculated cumulative contribution. The results of the analysis were visualized on the Pareto chart.

In turn, XYZ analysis allows you to analyze and predict the stability of certain business processes (business objects). For example, you can use it to determine the predictability of the behavior of different groups of customers or the stability of sales of certain types of goods. During the XYZ analysis, the coefficient of variation was calculated, then the drugs were grouped into three categories: category X – a group of products that are characterized by stable sales or consumption and high forecasting capabilities (the value of the coefficient of variation is in the range 0-10%), category Y – a group of products characterized by seasonal fluctuations and average forecasting capabilities (the value of the coefficient of variation is in the range of 10-25%), category Z is a group of products with irregular consumption, that is, there are difficulties in identifying trends, and low forecasting accuracy is characteristic (the value of the coefficient of variation is above 25%) [19, 20].

Next, an integrated ABC/XYZ analysis matrix was constructed, which allows us to get an idea of the place of each drug of the analyzed group in the assortment of pharmaceutical organizations, as well as to assess their contribution to the turnover and get an idea of the structure of use [21]. Such a matrix will help to adjust the existing modern range of antifungal drugs that are triazole derivatives for pharmaceutical organizations.

Microsoft Excel 2019 software was used for all types of analysis. Using this program, real-value distribution graphs, a Pareto chart, and an integrated ABC-XYZ matrix were constructed.

Results and Discussion

The modern pharmaceutical market is characterized by a steady growth of new medicines, the range of which is replenished, including due to the entry of combined drugs into the market. It is worth noting that currently a large number of generic drugs are registered, which have different trade names with the same active substances.

Previously, it was shown that today there are 1,432 antifungal drugs on the Russian pharmaceutical market, with the main market share being occupied by fluconazole - 22% and terbinafine – 16 % [22].

In the course of the research, all the analyzed antifungal drugs were grouped based on the chemical structure of the active substances (Figure 1). Combined drugs containing 2 or 3 active substances were assigned to the chemical group of the main therapeutically active component, or isolated separately if the combined drug did not contain a true antifungal agent (for example, antiseptics, broad-spectrum antibiotics, etc.). Triazole derivatives (3rd generation antimycotics) are the largest group represented by 360 drugs (26%). Next in the number of drugs are imidazole derivatives (antimycotics of the 2nd generation) 260 drugs (18%) and allylamines 213 drugs (15%). Among the truly antifungal active substances, the drug Griseofulvin accounts for only 3 drugs (in the total structure of the assortment, slightly more than 0%). A relatively large number of herbal medicines (117-8%), which is almost equal to the number of polyenes (119-8%). Thus, triazole derivatives occupy the first place in the structure of the assortment on the Russian pharmaceutical market.

ABC-analysis was used to analyze and identify the most priority positions of individual antimycotic drugs of the triazole derivatives group in the assortment of the modern Russian pharmaceutical market. For clarity, a Pareto chart with group subdivisions is built (Figure 2).

All drugs belonging to group A, and above all the leaders of this group, among which we can distinguish Diflucan («Pfizer»), Flucostat («OTCpharm» JSC), Vfend («Pfizer»), Fluconazole («Vertex» JSC) and Irunin («Veropharm» JSC), should always be present in the assortment of retail and wholesale participants of the Russian pharmaceutical market since they ensure maximum sales among drugs that are derivatives of triazole. The influence of all representatives of group A on the turnover of antifungal medicines is the greatest, so pharmacy organizations need to take this group of products into account first.

Group B drugs are «average» in importance in the range of antimycotics of the triazole derivatives group. These include Orungamin (LLC «Ozon»), Voriconazole Sandoz («Sandoz»), Mycosist (JSC «Gedeon Richter»), Rumycoz («Valenta Pharm»), Fluconazole-OBL (JSC «OBL Pharm»), Itraconazole (JSC «Synthez») and Biflurin (JSC «Pharmsynthez»). All of these drugs provide a stable sales volume, so investments from various market participants should be directed to maintaining the current level of sales of these antimycotics. In Group C, 18 representatives can be identified, with a share of up to 0.01% in the total contribution - these are the drugs Fluconazole (JSC R - Pharm, JSC Akrikhin, Alvis, Valenta, Astrapharm), Fluconazole-LEKSVM (LLC PROTEK-SVM), Mycoflucan («Dr. Reddy's Laboratories»), Vagisept (LLC FIRN M), Forcan («Dr. Reddy's Laboratories»), Fluconazole-Akti (LLC «Aktipharm»), Medoflucon («MEDOCHEMIE»), Procanazole («PROTECH BIOSYSTEMS»), Vero-Fluconazole (JSC «Veropharm»), Difluzol (JSC «OBL Pharm»), Vero-Fluconazole («Okasa Pharma»), Syscan («Torrent pharmaceuticals»), Flucostat (EP MBP RF), Myconil («Claris LiveScience»). These drugs are «outsiders» among the triazole derivatives on the market since their contribution to total sales is minimal to 0.01% or equal to 0. In this regard, it is advisable to remove the above drugs from the range of antifungal drugs.

The ABC analysis reflected the contribution of various antifungal drugs of the triazole derivatives group to the assortment of the Russian pharmaceutical market, as well as the impact on the turnover of pharmacies of various forms of ownership, but they cannot assess the frequency of purchase and seasonal fluctuations in demand. To do this, an XYZ analysis was performed. The coefficient of variation was calculated using the formula:

where v - is the coefficient of variation, xi- is the value of the parameter for the evaluated object for the i-th period, x - is the average value of the parameter for the evaluated object of analysis, n - is the number of periods. Further, based on the value of the obtained coefficients of variation of each drug (in%), the drugs were grouped into 3 groups: group X: 0-10%, group Y: 10-25%, group Z: over 25%. For clarity, a diagram of the distribution of all representatives of the triazole group (in percentage and quantitative terms) is constructed (Figure 3). Most of the drugs considered were classified as category Z.

During the research, an integrated matrix was compiled based on the results of ABC/XYZ analyses with the distribution of drugs into 9 categories: AX, AY, AZ, BX, BY, BZ, CX, CY, and CZ (Table 1).