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

Abstract

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.

Antituberculosis Macozinone Extended-Release Tablets To Enhance Bioavailability: a Pilot Pharmacokinetic Study in Beagle Dogs

“…The pharmacokinetics (PK) of macozinone immediate-release dispersible tablet for oral suspension in Beagle dogs after a single oral administration of 160 mg supported the primary in vitro findings on the narrow absorption window of the drug, the maximum drug concentration in plasma ( C max ) and the total drug exposure (AUC inf ) in the fed state are 1.8 and 1.3 times, respectively, higher than in the fasted states: absorption is confined to the upper gastrointestinal tract ( 9 ). In addition, macozinone is rapidly eliminated, the mean residence time (MRT last ) was low (3.6 h) and the half-life ( t 1/2 ) was short (3.2 h) ( 9 ). Guo and colleagues ( 10 ) reported low absolute bioavailability of macozinone ( F abs ~10%) in mice after a single oral administration of 12.5 or 25.0 mg/kg.…”

“…The antibacterial potency of benzothiazinone-based molecule derivatives is directly proportional to their lipophilicity ( 4 ), but the high lipophilicity of a drug contributes to its poor water solubility and variable oral bioavailability ( 8 ). Moreover, the water solubility of macozinone strongly depends on the pH level: it highly dissolves in strongly acidic solutions (pH ~1 to 2) and poorly dissolves in moderately acidic solutions (pH ~5 to 6) ( 9 ). In biorelevant media, macozinone is more soluble in fed-state simulated intestinal fluid (FeSSIF) than in fasted-state simulated intestinal fluid (FaSSIF).…”

“…Further, MCZ shows low permeability in the Caco-2 assay (an early drug discovery assay that uses a human colon epithelial cancer cell line as a model for human intestinal absorption of an experimental compound) with an efflux ratio of 0.6 ( 9 ). The pharmacokinetics (PK) of macozinone immediate-release dispersible tablet for oral suspension in Beagle dogs after a single oral administration of 160 mg supported the primary in vitro findings on the narrow absorption window of the drug, the maximum drug concentration in plasma ( C max ) and the total drug exposure (AUC inf ) in the fed state are 1.8 and 1.3 times, respectively, higher than in the fasted states: absorption is confined to the upper gastrointestinal tract ( 9 ). In addition, macozinone is rapidly eliminated, the mean residence time (MRT last ) was low (3.6 h) and the half-life ( t 1/2 ) was short (3.2 h) ( 9 ).…”

“…1 ). According to the Biopharmaceutical Classification System, macozinone is considered a class IV drug owing to its low water solubility and permeability ( 9 ). Hence, MCZ has been proposed as a suitable candidate for a mucoadhesive gastroretentive (or extended-release [ER]) drug delivery system.…”

Optimized LC-MS/MS quantification of tuberculosis drug candidate macozinone (PBTZ169), its dearomatized Meisenheimer Complex and other metabolites, in human plasma and urine

“…PBTZ169 has successfully passed preclinical safety, toxicology and pharmacokinetic [26] assessments, and ascending dose Phase I and Phase II trials taking place both in Russia [27] , and in Switzerland (study name: IM-006–11 and IM-006–13, ClinicalTrials.gov identifier: NCT03776500 and NCT03423030). An analytical method by tandem mass spectrometry was developed by our group for the quantification of macozinone and five active metabolites in plasma samples collected during the first pharmacokinetic studies performed at the Lausanne Hospital Center [28] .…”