## 5 From PBTZ169 to Macozinone: First Results of the Clinical Studies
These data agree with the results of in vitro studies, which were conducted by Nearmedic Plus LLC, assessing cellular permeability and solubility in biorelevant media, which mimicked native gastric and intestinal juices. They confirmed that the highest solubility of PBTZ169 is observed at the pH range of 1 to 2, which coincides with the pH in the lower part of the stomach, and its solubility gradually decreases with the growing pH. In the media with pH higher than 5, PBTZ169 was virtually insoluble. According to the test of solubility in biorelevant media, the drug level in the gastric juice was much higher than in the intestinal juice. So, one of the possible methods to increase bioavailability and exposure of PBTZ169 is to prolong its presence in the stomach. After a single fasting dose, PBTZ169 absorbed rapidly, and the speed of absorption was independent of the administered dose (median T\({}_{\text{max}}\) was 1.5-2.5 hours for the dose range 40-640 mg (NCT03036163), and 1.5-1.75 hours for the dose range 640-1280 mg (NCT04150224). Meantime of retention of the drug in the body was 13.02-19.30 hours and was independent of the administered dose (NCT03036163) [22]. According to the obtained pharmacokinetic data, dose proportionality of C\({}_{\text{max}}\) and AUC\({}_{\text{0-t}}\) was demonstrated for single, as well as for multiple administrations of the investigational drug in the dose range 40-640 mg (NCT03036163, NCT03334734). After single fasting escalating doses (640, 960, and 1280 mg), C\({}_{\text{max}}\), AUC\({}_{\text{0-24}}\), AUC\({}_{\text{0-\infty}}\) were less than dose proportional. Thus, it can be concluded that there is a trend for linear pharmacokinetics for single and multiple doses up to 640 mg. When pharmacokinetics of different administration regimens for 1280 mg daily dose was studied (640 mg twice daily or 1280 mg once in fasting conditions), the pharmacokinetic parameters AUC\({}_{\text{0-\infty}}\) and AUC\({}_{\text{0-t}}\) increased 1.5-1.6-fold (NCT04150224). The relation of mean AUC\({}_{\text{0-\infty}}\) and AUC\({}_{\text{0-t}}\) in cohorts receiving the investigational drug as 640 mg twice a day and 1280 mg once a day, was 153.68% and 160.32%. For C\({}_{\text{max}}\), a slight decrease (1.1-fold) was observed for the 640 mg twice a day (the relation of means was 90.84%). All observed differences were statistically significant. According to the results of analysis of relative bioavailability and relative degree of absorption, the main pharmacokinetic parameters of PBTZ169 substantially and statistically significantly increased when 640 mg dose was administered in fed conditions: AUC\({}_{\text{0-\infty}}\)increased 3.45-fold, AUC\({}_{\text{0-t}}\) (f') increased 3.50-fold, C\({}_{\text{max}}\) increased 2.29-fold. The drug absorbed and cleared from the body significantly more slowly, when it was administered in fed conditions compared to the fasting conditions (median T\({}_{\text{max}}\)increased 2-fold, mean T\({}_{1/2}\) increased 1.44-fold). These data allow to conclude that it is preferable to administer PBTZ169 in fed conditions [22]. In October 2018, the international non-proprietary name \"macozinone\" was given to PBTZ169 by WHO [28]. In addition to the clinical studies, macozinone is undergoing further in vitro and in vivo testing focused on improvement of its pharmacological properties by structure-based design [29], or on the interactions with anti-TB drugs [30]. Importantly, an efficient method for monitoring metabolism of macozinone in human plasma was recently developed. It enables simultaneous measurement of concentrations of macozinone and its five active metabolites in the clinical samples, which is important for comprehensive pharmacokinetic/pharmacodynamic analyses [31].