| Summary: | Pharmacometric analysis is often used to quantify the differences and similarities between formulation prototypes. In the regulatory framework, it plays a significant role in the evaluation of bioequivalence. While non-compartmental analysis provides an unbiased data evaluation, mechanistic compartmental models such as the physiologically-based nanocarrier biopharmaceutics model promise improved sensitivity and resolution for the underlying causes of inequivalence. In the present investigation, both techniques were applied to two nanomaterial-based formulations for intravenous injection, namely, albumin-stabilized rifabutin nanoparticles and rifabutin-loaded PLGA nanoparticles. The antibiotic rifabutin holds great potential for the treatment of severe and acute infections of patients co-infected with human immunodeficiency virus and tuberculosis. The formulations differ significantly in their formulation and material attributes, resulting in an altered biodistribution pattern as confirmed in a biodistribution study in rats. The albumin-stabilized delivery system further undergoes a dose-dependent change in particle size which leads to a small yet significant change in the in vivo performance. A second analysis was conducted comparing the dose fraction-scaled pharmacokinetic profiles of three dose levels of albumin-stabilized rifabutin nanoparticles. The dose strength affects both the nanomaterial-related absorption and biodistribution of the carrier as well as the drug-related distribution and elimination parameters, increasing the background noise and difficulty of detecting inequivalence. Depending on the pharmacokinetic parameter (e.g., AUC, C<sub>max</sub>, Cl<sub>obs</sub>), the relative (percentage) difference from the average observed using non-compartmental modeling ranged from 85% to 5.2%. A change in the formulation type (PLGA nanoparticles vs. albumin-stabilized rifabutin nanoparticles) resulted in a similar level of inequivalence as compared to a change in the dose strength. A mechanistic compartmental analysis using the physiologically-based nanocarrier biopharmaceutics model led to an average difference of 152.46% between the two formulation prototypes. Albumin-stabilized rifabutin nanoparticles tested at different dose levels led to a 128.30% difference, potentially due to changes in particle size. A comparison of different dose strengths of PLGA nanoparticles, on average, led to a 3.87% difference. This study impressively illustrates the superior sensitivity of mechanistic compartmental analysis when dealing with nanomedicines.
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