Population pharmacokinetics and pulmonary modeling of eravacycline and the determination of microbiological breakpoint and cutoff of PK/PD.

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 ([Formula: see text], 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. MIC₉₀ 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.