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Antituberculosis Macozinone Extended-Release Tablets To Enhance Bioavailability: a Pilot Pharmacokinetic Study in
Angela Koryakova1, Victoria Shcherbakova2, Olga Riabova3
1Chemical Diversity Research Institute, Khimki, Russia.
Abstract:
Macozinone (MCZ; PBTZ169) is a first-in-class antituberculosis clinical-stage benzothiazinone-based drug candidate. Although its efficacy and safety have been strongly proven in several preclinical and clinical studies, the physicochemical and pharmacokinetic properties specific to MCZ required further optimization. Accordingly, this study aimed to evaluate the pharmacokinetics of MCZ administered as extended-release (ER) tablets F2 and F6 compared to immediate-release (IR) dispersible tablets for oral suspension. Oral absorption of MCZ from ER tablets was significantly different from that of IR tablets after a single oral dose in Beagle dogs in both fasted and fed states. In addition, food directly affects the bioavailability of MCZ from ER tablets but does not affect it from IR tablets. The high values of relative bioavailability of the prolonged-release tablets F2 and F6 compared to the IR tablets may indicate an indirect confirmation of their gastroretentive properties. Taken together, pharmacokinetic parameters have demonstrated that these MCZ oral formulations not just enhance drug bioavailability but may also improve regimen adherence by reducing MCZ dose frequency and reducing the development of drug resistance. IMPORTANCE Macozinone (MCZ) is the newest first-in-class clinical-stage benzothiazinone-based drug candidate for the treatment of tuberculosis. Yet, the extremely low oral bioavailability of MCZ, a major problem in clinical trials, needed to be addressed, and we are pleased to present our attempts to solve this issue. We report that extended-release tablets of MCZ significantly increased key pharmacokinetic parameters in the preclinical setting. We suggest that these MCZ oral formulations not just enhance drug bioavailability but may also improve regimen adherence by reducing MCZ dose frequency and reducing the development of drug resistance.
Insights
Extended-release Macozinone (MCZ) tablets significantly improved oral bioavailability and pharmacokinetic parameters in dogs. These new formulations may enhance tuberculosis treatment adherence by reducing dosing frequency.
Area of Science:
- Pharmacology
- Drug Development
- Tuberculosis Research
Background:
- Macozinone (MCZ) is a promising first-in-class antituberculosis drug candidate.
- Low oral bioavailability of MCZ presents a challenge in clinical settings.
- Optimization of MCZ's pharmacokinetic properties is crucial for effective tuberculosis treatment.
Purpose of the Study:
- To evaluate the pharmacokinetics of extended-release (ER) MCZ tablets (F2 and F6) compared to immediate-release (IR) dispersible tablets.
- To assess the impact of food on the absorption of MCZ from different oral formulations.
- To investigate the potential of ER formulations to improve MCZ bioavailability and therapeutic outcomes.
Main Methods:
- Pharmacokinetic evaluation of MCZ ER (F2, F6) and IR tablets in Beagle dogs.
- Administration of single oral doses in both fasted and fed states.
- Comparison of key pharmacokinetic parameters, including bioavailability and absorption profiles.
Main Results:
- MCZ ER tablets demonstrated significantly different oral absorption compared to IR tablets.
- Food intake affected the bioavailability of MCZ from ER tablets but not IR tablets.
- ER formulations exhibited high relative bioavailability, suggesting gastroretentive properties.
Conclusions:
- Extended-release formulations of Macozinone (MCZ) significantly enhance drug bioavailability.
- These novel MCZ oral formulations may improve treatment adherence by reducing dosing frequency.
- Optimized MCZ delivery could mitigate the development of drug resistance in tuberculosis treatment.
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