ABSTRACT Eravacycline is a broad-spectrum fluorocycline currently approved for complicated intra-abdominal infections (cIAIs). In lung-infection models, it is effective against methicillin-resistant Staphylococcus aureus (MRSA) and tetracycline-resistant MRSA. As such, we aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model to evaluate eravacycline’s pulmonary distribution and kinetics. Data were extracted from a Phase I study ( NCT01989949 ) which assessed the bronchopulmonary disposition of intravenous eravacycline to construct the population PK model that could adequately describe the drug’s pulmonary kinetics. Eravacycline lung PK was best described by a three-compartment model with allometric scaling, with the epithelial lining fluid (ELF) component parameterized as the ELF distribution ratio ( R a t i o = C f r e e , E L F C f r e e , c e n t r a l , unbound concentration in ELF over central compartment). The estimated ELF distribution ratio was 8.26 (95% confidence interval = 6.8–9.8). Besides allometrically scaled weight, no other significant covariate was found. MIC 90 was 0.5 mg/L ( Escherichia coli ), 2 mg/L ( Klebsiella pneumoniae ), 0.5 mg/L ( Acinetobacter baumannii ), and 0.12 mg/L ( S. aureus ). At the approved cIAI dosage or higher (1 mg/kg or 1.5 mg/kg q12h), a PK/PD cutoff value of 2 mg/L was appropriate for E. coli , while a lower value of 1 mg/L was selected for K. pneumoniae , A. baumannii , and S. aureus . For lower doses, the cutoff value was reduced to 0.5 mg/L for K. pneumoniae , A. baumannii , and S. aureus . The study showed eravacycline was widely distributed into the lungs with promising antibacterial efficacy, thus justifying further investigations into its uses for pulmonary infections.

Isabelle Kuan

Publications