Dose optimization of omadacycline for the treatment of nontuberculous mycobacterial pulmonary disease (NTM-PD) using a physiologically based pharmacokinetic modeling approach

초록

Purpose Nontuberculous mycobacterial pulmonary disease (NTM-PD) presents growing challenges due to rising prevalence, antimicrobial resistance, and poor treatment outcomes. Omadacycline shows potential as a treatment option given its broad-spectrum activity, oral bioavailability, and high pulmonary penetration, yet optimal dosing remains unclear. This study aimed to develop a permeability-limited multi-compartment lung physiologically based pharmacokinetic (PBPK) model of omadacycline to predict epithelial lining fluid (ELF) concentrations and support pharmacokinetic/pharmacodynamic (PK/PD)-based dose optimization for NTM-PD. Methods A whole-body PBPK model was developed using Simcyp (R) v24 and validated against 25 clinical pharmacokinetic studies. The model was then extended to incorporate detailed pulmonary compartments and transporter-mediated efflux, and simulated ELF concentrations were verified using clinical bronchoalveolar lavage data. Monte Carlo simulations were conducted to estimate ELF exposures and probability of target attainment (PTA) for three oral omadacycline regimens (300, 450, and 600 mg QD). Results PK/PD target attainment analysis showed that a 300 mg once-daily oral dose of omadacycline is sufficient to achieve target attainment for pathogens with MICs <= 0.5 mg/L, corresponding to MIC90 values. The cumulative fraction of response (CFR) was lower in cystic fibrosis (CF)-derived isolates than in non-CF isolates. Conclusion These results support the efficacy of 300 mg omadacycline against the majority of strains (93% of isolates) and demonstrate the utility of PBPK modeling in optimizing omadacycline regimens for NTM-PD.

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