In Vitro Action of the Drug Candidate of Pbtz169, Hydrochloride Action in Respect of Clinical Strains of Mycobacterium Tuberculosis With Extensive Drug Resistance

Черноусова, Л. Н.; Андреевская, С.Н.; Смирнова, Т. Г.; Ларионова, Е. Е.; Андриевская, И. Ю.; Shevkun, Natalia A.

doi:10.21292/2075-1230-2016-94-9-73-79

Cited by 5 publications

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“…117 PBTZ169 was used as hydrochloride salt. 119,120 Koryakova et al mentioned that various water-soluble salts, the use of surfactants or particle size reduction failed to improve This journal is © The Royal Society of Chemistry 2023 the bioavailability of PBTZ169. 120 Li et al, however, reported some progress for the benzothiopyranone analogue of PBTZ169 through solubility-driven optimization of salt forms with pharmaceutically acceptable anions.…”

Section: Physicochemical and Pharmacokinetic Propertiesmentioning

confidence: 99%

Synthesis, structures, reactivity and medicinal chemistry of antitubercular benzothiazinones

et al. 2023

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Section: Physicochemical and Pharmacokinetic Propertiesmentioning

confidence: 99%

Synthesis, structures, reactivity and medicinal chemistry of antitubercular benzothiazinones

et al. 2023

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“…В проведенных исследованиях на базе Центрального научно-исследовательского института туберкулеза (Москва) продемонстрирована крайне высокая специфическая активность PBTZ169 (бактериостатическая и бактерицидная) в отношении МЛУ/ШЛУ-штаммов, в том числе в отношении самых опасных штаммов МБТ, большинство из которых были устойчивы как минимум к 9 основным и резервным ПТП. Кроме того, при инкубации in vitro с PBTZ169 в концентрации 0,037 мкг/мл происходило полное подавление роста всех штаммов, выделенных от ВИЧ-негативных и от большинства ВИЧ-инфицированных больных [15].…”

Section: ââåäåíèåunclassified

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

Mariandyshev

Khokhlov²,

Smerdin³

et al. 2020

Terapevticheskii arkhiv

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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.

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“…Уникальность мишени макозинона обеспечивает его высокую активность in vitro (бактериостатическую и бактерицидную) в отношении не только стандартных форм ТБ, но и в отношении мультирезистентных форм (МЛУ/ШЛУштаммы, в том числе самые опасные штаммы МБТ, большинство из которых устойчивы как минимум к 9 основным и резервным ПТП), что показано в специально проведенных исследованиях [15]. Кроме того, при инкубации in vitro с PBTZ169 в концентрации 0,037 мкг/мл происходило полное подавление роста всех штаммов, выделенных от ВИЧ-негативных и большинства ВИЧ-инфицированных больных [16].…”

Section: ââåäåíèåunclassified

“…В проведенных исследованиях in vivo по созданию новых форм комбинированных режимов терапии ТБ путем совместного применения макозинона с новейшим зарегистрированным ПТП -бедаквилином и пиразинамидом -показан синергетический эффект антимикобактериальной активности [13][14][15]; выявлено его синергическое взаимодействие с клофазимином, деламанидом и сутезолидом [16,17] и аддитивное -с претоманидом, изониазидом, моксифлоксацином, рифампицином и SQ-109 [17]. Важно отметить, что в этих исследованиях не обнаружены ни антагонизм, ни повышенная токсичность исследуемых комбинаций [16].…”

Section: ââåäåíèåunclassified

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

Khokhlov¹,

Mariandyshev

Щербакова³

et al. 2020

Terapevticheskii arkhiv

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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.

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In Vitro Action of the Drug Candidate of Pbtz169, Hydrochloride Action in Respect of Clinical Strains of Mycobacterium Tuberculosis With Extensive Drug Resistance

Cited by 5 publications

References 0 publications

Synthesis, structures, reactivity and medicinal chemistry of antitubercular benzothiazinones

Synthesis, structures, reactivity and medicinal chemistry of antitubercular benzothiazinones

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

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

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