Tuberculosis is a chronic infectious disease, usually localized in the respiratory system and representing one of the most important global social and biomedical health problems associated with the spread of therapy-resistant forms (multidrug-resistant and extensively drug-resistant tuberculosis). One of the most promising targets for the development of antimycobacterial drugs is the enzyme DprE1, which is involved in the synthesis of the cell wall of mycobacteria. In the series of DprE1 inhibitor drugs, the most advanced drug is PBTZ169 (INN maсozinone). Clinical trials (CT) of the efficacy and safety of macozinone are conducted by the pharmaceutical company LLC NEARMEDIC PLUS in the Russian Federation, and in other countries (Sponsors: Innovative Medicines for Tuberculosis Foundation, cole polytechnique fdrale de Lausanne and Bill and Melinda Gates Foundation). The publication describes results of completed I, IIa and Ib phases CT, conducted in the Russian Federation. Aim. The goal of phase I CT was to assess the safety, tolerability and pharmacokinetics (PK) of PBTZ169, 40 mg capsule, after single and multiple administration under fasting conditions in increasing doses in healthy volunteers. The goal of phase IIa CT was to study the efficacy (in terms of early bactericidal activity EBA), safety and PK of the drug PBTZ169, 80 mg capsules, in various doses, when used as monotherapy in patients with newly diagnosed respiratory tuberculosis with bacterial excretion and retained sensitivity to isoniazid and rifampicin. The purpose of phase Ib CT was to evaluate the safety, tolerability, PK of PBTZ169, 80 mg capsule, after single, double and multiple administration under fasting conditions in increasing doses, as well as the effect of food on its bioavailability in healthy volunteers. Materials and methods. The data of 100 healthy volunteers and 15 patients with newly diagnosed pulmonary tuberculosis, who received the study medication PBTZ169, capsules 40 mg and 80 mg, in the dose range 40 mg 1280 mg of PBTZ169, obtained during phase I, IIa and Ib CTs were analyzed. During I phases CTs, safety, tolerability, and PK of the drug after a single and multiple administration under fasting condition and after meals at rising doses were evaluated. The safety assessment included evaluation of AE/SAE, vital signs, ECG results, and laboratory tests results in the safety population. In the course of phase IIa CT, in addition to safety, tolerance, and PK evaluation, the efficacy of the drug (in terms of EBA) using sputum culture on agar with CFU/ml counting (main method) and quantitative PCR method (auxiliary method) was evaluated. Results. During all CTs, a high safety and tolerability profile was shown, the main PK parameters of the drug and the efficacy were described. PBTZ169 demonstrated linear PK in the dosage range up to 640 mg after single and multiple administration, a statistically significant of EBA of the drug after monotherapy at the dose of 640 mg/day was demonstrate, and it was concluded that the preferred regimen of the drug PBTZ169 intake is administration after meals. Good tolerability and a favorable safety profile of the drug in the studied doses range were demonstrate during all the CTs. Conclusion. One of the most promising and currently studied drugs-inhibitors of DprE1, a new target for the cell wall of mycobacteria, is PBTZ169 or macozinone, which is being develop by the Russian pharmaceutical company NEARMEDIC PLUS ltd.

Introduction. Due to increase in the frequency of detecting cases of tuberculosis caused by strains of mycobacteria with resistance not only to traditional, but also recently introduced into clinical circulation anti-tuberculosis drugs, it is urgent to search for and develop new drugs that can be effective against multidrug-resistant (MDR-TB) and extensively drug resistant (XDR-TB) strains. One of the most promising classes of such compounds are fluorine derivatives of benzothiazinones, and particularly compound PBTZ169 (INN macozinone). This antibiotic has a high specificity against mycobacteria tuberculosis (M. tuberculosis), inhibiting one of the key enzymes of cell wall synthesis. However, macozinone as an active pharmaceutical ingredient has significant features of physical and chemical properties that hinder the development of oral dosage forms based on it. It is classified as class IV by BCS and is characterized by a very low solubility and lipophilicity, a pronounced dependence of dissolution rate on the pH of the medium, and very low bioavailability when taken orally.Aim. To substantiate the target profile, critical quality attributes and to develop a prototype of an oral dosage form with modified release of macozinone, allowing to maximize its pharmacological activity.Materials and methods. Using pharmaceutical substance macozinone hydrochloride and various excipients, experimental tablets with a dosage of 500 mg macozinone were developed. The influence of the composition of the media and the added excipients on the solubility of macozinone in various biorelevant media, the degree of swelling in the liquid and the degree of mucoadhesion of the experimental tablets to the mucus of the pig stomach were evaluated. The HPLC method was used to evaluate the kinetics of the release of the active substance.Results and discussion. In this work, the expediency of creating macozinone-containing gastro-retentive dosage forms with a slow release of the active substance, the delay mechanism of which is provided by swelling and increased adhesion to the gastric mucosa, has been substantiated. Various tablet samples were experimentally tested in which the modification of the release of the active substance and the degree of swelling and mucoadhesion were varied by introducing various excipients into the formulations, including known swelling and bioadhesive matrix agents.Conclusion. According to the results of the experiments, samples of high-dose (500 mg) swellable and mucoadhesive tablets created by the technology of two-stage granulation with the inclusion of macozinone - hydroxypropyl-beta-cyclodextrin mixtures in the primary granules and introduction of combinations of soluble and insoluble hydrophilic matrix agents into the intergranular space were recognized as the most promising for subsequent pharmacokinetic studies.