A phase I clinical study: evaluation of safety, tolerability, and population pharmacokinetic-pharmacodynamic target attainment analysis of etimicin sulfate among healthy Chinese participants

This phase I clinical study aimed to assess the safety, tolerability, and population pharmacokinetic-pharmacodynamics (PK-PD) target attainment analysis of etimicin sulfate in healthy participants, and to provide scientific reference for further development of clinical breakpoints. A total of 24 healthy Chinese subjects were enrolled in this study and received an etimicin sulfate infusion. A population PK model was constructed for the estimation of the PK profiles of etimicin sulfate. The area under the concentration-time curve divided by the minimum inhibitory concentration (AUC0-24h/MIC) and the peak concentration divided by the MIC (Cmax/MIC) were selected as the PK/PD indices. The probability of target attainment (PTA) was calculated for each designed dosing regimen using Monte Carlo simulations. The minimum MIC value with a PTA ≥ 90% for each regimen was considered as the PK/PD cutoff values. Etimicin sulfate demonstrated safety, tolerability, and predictable PK characteristics. No deaths or serious adverse events were reported. Seven treatment-emergent adverse events (TEAEs) were reported by five participants; all TEAEs were minor and were rapidly relieved. A two-compartment model was developed and validated for describing the PK features of etimicin sulfate among Chinese healthy participants. The diagnostic goodness-of-fit plots and visual predictive check plots showed that this developed model could describe these data well. The PTA results showed that etimicin sulfate provided clinical improvement against strains with an MIC of 0.5-1 mg/L and below, and antibacterial effect against strains with an MIC of 0.25 mg/L and below. However, etimicin sulfate had limited clinical efficacy for clinical isolates with MIC values > 1 mg/L.