A Comparative Pharmacokinetics Study of Orally and Intranasally Administered 8-Nitro-1,3-benzothiazin-4-one (BTZ043) Amorphous Drug Nanoparticles

BTZ043 is an 8-nitro-1,3-benzothiazin-4-one with potency against multidrug-resistant Mycobacterium tuberculosis. Low solubility and hepatic metabolism are linked to poor oral bioavailability. Amorphous drug nanoparticles (ADN) were formulated to improve the bioavailability. Comparative pharmacokinetics of BTZ043 ADN following intranasal (2.5 mg kg${–1}$) and oral administration (25 mg kg${–1}$) in Balb/c mice was investigated using oral BTZ043 drug suspensions (neat; 25 mg kg${–1}$) as a standard-of-care reference. Plasma exposure following oral ADN administration was 8-fold higher than for oral neat BTZ043. Intranasal ADN increased plasma exposure 18-fold compared to oral neat BTZ043 after dose normalization. BTZ043 was detectable in lung lining fluid following ADN administration, but not after oral neat BTZ043 dosing. BTZ043 was cleared faster from the lung and plasma following intranasal administration with a shorter time above the minimum inhibitory concentration (MIC) compared to oral ADN. Since time > MIC is reported to drive activity, oral ADN may represent a promising delivery strategy for BTZ043.