[The main results of clinical trials of the efficacy, safety and pharmacokinetics of the perspective anti-tuberculosis drug makozinone (PBTZ169)].

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.

[Effect of physicochemical properties on the pharmacokinetic parameters of the new representative of benzothiazinones antituberculosis drug macozinonе].

INTRODUCTION: Tuberculosis (TB) is one of the top ten causes of death worldwide. Improvement of the treatment options via development of new drugs and treatment regimens that would be more convenient for patients is one of key options of improving the effecacy of the TB prevention and careis. Since the creation of new treatment regimens by minimizing the number of the drugs used and reducing the duration of treatment is the most promising and correct direction, macozinone, a new candidate of the benzothiazinone series, can become the basis for development of new chemotherapy regimens for drug-resistant forms of TB including the combination of macozinone with the most effective modern anti-TB drugs. AIM: Comparative evaluation of the pharmacokinetic properties of macozinone capsules 80 mg and the new dosage form a dispersible tablet for preparation of oral solution. MATERIALS AND METHODS: Solubility of the substance macozinone in biorelevant media in vitro, permeability of macozinone in the test Caco-2 in vitro, as well as pharmacokinetics of macozinone in dogs in vivo were evaluated. RESULTS: The solubility assessment in biorelevant media showed that the average limit of macozinone substance dissolution in the pH 5.0 acetate buffer solution was from 6 to 9 mg/l, in FaSSIF medium (fasted) from 2.5 to 4 mg/l, and in FeSSIF medium (after meals) from 16.8 to 29 mg/l. It is established that the cell permeability of the pharmaceutical substance macozinone in the CACO-2 test system is on average 2.510-6cm/s in the forward direction from the apical to basolateral cell membrane, and 1.510-6cm/s in the reverse direction, which corresponds to low permeability. The main pharmacokinetic parameters of macozinone dispersable tablets 160 mg, after dosing with food and on an empty stomach, as well as capsules 80 mg, when administered on an empty stomach in vivo studies in dogs are presented. DISCUSSION: The specific physicochemical properties of macozinone, the problems of developing the new dosage form, as well as ways of solving some of them are presented. CONCLUSION: In the process of new dosage forms development, the existing chemical properties of the macozinone substance should be considered. One of the promising ways of increasing bioavailability and, consiquently, efficacy is development a fundamentally new drug form with modified release within the absorption window.

Cost minimization analysis of line probe assay for detection of multidrug-resistant tuberculosis in Arkhangelsk region of Russian Federation.

BACKGROUND: The development of new diagnostic tools allows for faster detection of both tuberculosis (TB) and multidrug-resistant (MDR) TB and should lead to reduced transmission by earlier initiation of anti TB therapy. The research conducted in the Arkhangelsk region of the Russian Federation in 2012-14 included economic evaluation of Line Probe Assay (LPA) implementation in MDR-TB diagnostics compared to existing culture-based diagnostics of Löwenstein Jensen (LJ) and BacTAlert. Clinical superiority of LPA was demonstrated and results were reported elsewhere. STUDY AIM: The PROVE-IT Russia study aimed to report the outcomes of the cost minimization analysis. METHODS: Costs of LPA-based diagnostic algorithm (smear positive (SSm+) and for smear negative (SSm-) culture confirmed TB patients by Bactec MGIT or LJ were compared with conventional culture-based algorithm (LJ-for SSm- and SSm+ patients and BacTAlert-for SSm+ patients). Cost minimization analysis was conducted from the healthcare system, patient and societal perspectives and included the direct and indirect costs to the healthcare system (microscopy and drug susceptibility test (DST), hospitalization, medications obtained from electronic medical records) and non-hospital direct costs (patient's travel cost, additional expenses associated with hospitalization, supplementary medicine and food) collected at the baseline and two subsequent interviews using the WHO-approved questionnaire. RESULTS: Over the period of treatment the LPA-based diagnostic corresponded to lesser direct and indirect costs comparing to the alternative algorithms. For SSm+ LPA-based diagnostics resulted in the costs 4.5 times less (808.21 US$) than LJ (3593.81 US$) and 2.5 times less than BacTAlert liquid culture (2009.61 US$). For SSm- LPA in combination with Bactec MGIT (1480.75 US$) vs LJ (1785.83 US$) showed the highest cost minimization compared to LJ (2566.09 US$). One-way sensitivity analyses of the key parameters and threshold analyses were conducted and demonstrated that the results were robust to variations in the cost of hospitalization, medications and length of stay. CONCLUSION: From the perspective of Russian Federation healthcare system, TB diagnostic algorithms incorporating LPA method proved to be both more clinically effective and less expensive due to reduction in the number of hospital days to the correct MDR-TB diagnosis and treatment initiation. LPA diagnostics comparing conventional culture diagnostic algorithm MDR-TB was a cost minimizing strategy for both patients and healthcare system.

Incidence of tuberculosis and associations with indicators of alcohol consumption in three regions of northwest Russia in 1975-2009: a time-series analysis.

BACKGROUND: Alcohol has several social consequences that are associated with increased risk of tuberculosis. However, there have been no studies assessing the links between tuberculosis and alcohol consumption in northwest Russia. The aim of this study was to assess associations between the incidence of tuberculosis and indicators of alcohol consumption in three regions of northwest Russia. METHODS: The study was performed in Arkhangelsk, Murmansk and Vologda regions using the data from 1975 to 2009. Deaths from alcohol poisoning and the incidence of alcohol psychoses were used as indicators of alcohol consumption. Associations between the incidence of tuberculosis and the above mentioned indicators were studied using time-series analysis. RESULTS: We identified significant positive associations between the incidence of tuberculosis and the incidence of alcohol psychoses in the same year in Arkhangelsk region (ß = 0.24, 95% CI: 0.10-0.37) and in Vologda region (ß = 0.18, 95% CI: 0.10-0.25), but not in Murmansk region. CONCLUSIONS: We found an association between the incidence of alcohol psychoses and the incidence of tuberculosis in the same year in Arkhangelsk and Vologda regions suggesting an indirect link between excessive levels of alcohol consumption and the incidence of tuberculosis in Russia.

Molecular epidemiology and drug resistance of widespread genotypes of Mycobacterium tuberculosis in northwestern Russia.

SETTING: Four administrative territories (Archangel Oblast, Murmansk Oblast, Republic of Karelia, Republic of Komi) in the northwestern federal region of Russia. OBJECTIVE: To describe the genetic diversity and level of drug resistance in Mycobacterium tuberculosis isolates from new cases of pulmonary tuberculosis. DESIGN: A total of 176 isolates of M. tuberculosis were tested for drug susceptibility and typed with insertion sequence (IS) 6110 restriction fragment length polymorphism (RFLP) and spoligotyping. RESULTS: The Beijing family was found to be the most prevalent (47.1%), most frequently clustered and significantly associated with drug resistance to all first-line anti-tuberculosis drugs (isoniazid, rifampicin, ethambutol, streptomycin and pyrazinamide) and ethionamide, when compared to the T and Haarlem families of M. tuberculosis, which were also prevalent in the study population. Some RFLP clusters (4/10) included isolates that originated from patients residing in different territories, and cases infected with multiple strains of M. tuberculosis were apparently present in the collection. CONCLUSION: The M. tuberculosis population in northwestern Russia appears to be genetically diverse and geographically widespread. Although dominated by isolates assigned to the Beijing family, other families also contribute to the current epidemic, and multiple strain infections may represent a problem in many cases. Extended genetic studies should be encouraged.

Resistance of multidrug-resistant strains of Mycobacterium tuberculosis from the Archangel oblast, Russia, to second-line anti-tuberculosis drugs.

Multidrug-resistant tuberculosis has become common all over the world, necessitating the inclusion of second-line drugs in treatment regimens. In the present study, the susceptibility of a selection of multidrug-resistant strains of Mycobacterium tuberculosis isolated in the Archangel oblast, Russia, to second-line anti-tuberculosis drugs was analysed. Susceptibility testing of 77 Mycobacterium tuberculosis strains was performed by the Bactec method using the following recommended drug concentrations: capreomycin 1.25 microg/ml; ethionamide 1.25 microg/ml; kanamycin 5 microg/ml; and ofloxacin 2 microg/ml. The majority of strains (92.2%) were resistant to ethionamide. High rates of drug resistance were also found for capreomycin (42.9%) and kanamycin (41.6%), while nearly all strains (98.7%) were susceptible to ofloxacin. The high rates of resistance to ethionamide, capreomycin, and kanamycin show the real burden of drug resistance in the region and pose a serious problem for the treatment of patients with multidrug-resistant tuberculosis.

Impact of drug-resistant Mycobacterium tuberculosis on treatment outcome of culture-positive cases of tuberculosis in the Archangel oblast, Russia, in 1999.

The objective of this study was to evaluate the outcome of treatment of culture-positive cases of tuberculosis registered in Archangel, Russia, in 1999, and to analyse the influence of Mycobacterium tuberculosis drug resistance on treatment outcome. The outcome of tuberculosis treatment was evaluated for 235 new and 61 previously treated culture-positive cases diagnosed in 1999. Of the 235 new cases, there were 150 (63.8%) cases of treatment completion, 20 (8.5%) cases of treatment failure, 29 (12.3%) cases of death during treatment, and 29 (12.3%) cases in which the patient failed to pick up medications for at least 2 consecutive months. The outcome in 7 (3%) cases was unknown, as the patients were transferred outside the oblast region. Among the 61 previously treated cases, the rate of treatment completion was low (26.2%), and rates of treatment failure (23%) and failure to pick up medications for at least 2 consecutive months (29.5%) were high. The relation between the susceptibility pattern of the infecting strain as determined by the Bactec method and tuberculosis treatment outcome was analysed for 76 patients. The majority (69%) of patients infected with drug-susceptible strains was cured. A large proportion (58.8%) of patients infected with Mycobacterium tuberculosis resistant to more than two drugs did not respond to treatment, i.e. the treatment failed or the patients died. The high rates of death (16.7%) and failure (66.7%) among patients infected with multidrug-resistant strains illustrate the negative impact of multidrug resistance on the outcome of tuberculosis treatment. Pan-resistance was significantly associated with treatment failure (P<0.001). The spread of resistant Mycobacterium tuberculosis has a serious negative impact on the outcome of tuberculosis treatment in Archangel, Russia.

Drug resistance of Mycobacterium tuberculosis strains isolated from patients with pulmonary tuberculosis in Archangels, Russia.

SETTING: The Archangels oblast, Russia, 1998-2000. OBJECTIVE: To study Mycobacterium tuberculosis resistance to anti-tuberculosis drugs in the Archangels oblast, and to reveal risk factors for the development of drug-resistant tuberculosis. DESIGN: The drug susceptibility of strains isolated from 119 patients with pulmonary tuberculosis was studied using the BACTEC method. Medical records of the patients were reviewed, retrospectively, to identify factors associated with drug resistance. RESULTS: Sixty-seven strains (56.3%) were resistant to at least one anti-tuberculosis drug. The highest rates of resistance were observed for streptomycin and isoniazid: respectively 40.4% and 66.7% of strains isolated from newly and previously treated patients were resistant to streptomycin, and respectively 37.1% and 73.3% of strains isolated from newly and previously treated patients were resistant to isoniazid. Thirty of the 119 strains (25.2%) were multidrug-resistant. Multidrug resistance was four times higher among previously treated patients than among new patients. A history of previous or interrupted treatment for tuberculosis and being female were significantly associated with drug resistance. CONCLUSION: Drug-resistant tuberculosis is an important problem in the Archangels oblast, Russia. The spread of drug resistance is attributed to several risk factors. Being female and evidence of previous treatment for tuberculosis are risk factors for the development of drug-resistant tuberculosis in the Archangels oblast. Patients with drug-resistant tuberculosis also showed a higher risk of interrupting their treatment.