Integrating Experimental Physicochemical Data with PBPK Modeling to Guide the Translational Development of the Antifungal 1,3,4-Oxadiazole Derivative LMM6

High Resolution Image Download MS PowerPoint Slide The rising mortality of invasive fungal infections highlights an urgent need for novel antifungal agents with improved translational profiles. The 1,3,4-oxadiazole derivative LMM6 has emerged as a promising candidate. Therefore, this study aimed to build a comprehensive biopharmaceutical profile of LMM6 and apply PBPK modeling as a rational tool in early drug development to evaluate its pharmacokinetic feasibility in mice and humans. In vitro biopharmaceutical experiments assessed solubility (shake-flask method) in compendial and biorelevant media, alongside experimental logP determination. ADME data were generated in silico and integrated into PBPK models. LMM6 exhibited a logP of 2.11 and low thermodynamic solubility across all media, though values slightly improved under acidic conditions and in the presence of bile salts. Mouse simulations (5 mg/kg q12h) predicted a plasma Cmax of ≈7.3 mg/L and an intracellular Cmax of 2.77 mg/L (kidney) and 1.21 mg/L (spleen), all below the minimum inhibitory concentration (MIC; 8–32 mg/L), with rapid declines and negligible troughs (Cmin < 0.1 mg/L). These findings suggest that previously reported mouse efficacy may not be fully explained by systemic exposure. Conversely, human PBPK extrapolation (700 mg q12h) predicted a more favorable profile, with interstitial renal and splenic concentrations reaching the MIC range from the third dose onward. While these in silico simulations suggest human exposures could surpass those in mice, these results remain hypothesis-generating and require further preclinical and clinical validation. This integrated approach provides critical translational insights for prioritizing formulation optimization and dosing strategies for this promising antifungal candidate.