Defining site-relevant PK/PD targets for nemonoxacin dosing in Streptococcus pneumoniae-associated community-acquired pneumonia through a translational PK/PD approach - PAGE Meeting (Population Approach Group Europe)

Yinru Chen ^1,2, Jinjin Zhao ¹, Size Li ¹, Xin Li ¹, Yuancheng Chen, Yi Li ¹, Yaxin Fan ¹, Jufang Wu ¹, Elizabeth C.M. de Lange ², Johan G.C. van Hasselt ², Tingjie Guo ², Jing Zhang ¹

1 Institute of Antibiotics, Huashan Hospital, Fudan University (Shanghai, China), 2 Leiden Academic Center for Drug Research, Leiden University (Leiden, the Netherlands)

Objectives
Nemonoxacin is a novel non-fluorinated quinolone demonstrating potent antibacterial activity against Streptococcus pneumoniae, the primary pathogen in community-acquired pneumonia (CAP). While current clinical dosing strategies are based on plasma pharmacokinetics (PK), they do not explicitly account for the PK/pharmacodynamic (PD) relationship at the epithelial lining fluid (ELF), the actual site of infection. This study aimed to characterize nemonoxacin exposure at the pulmonary site of infection, define site-relevant PK/PD targets in both plasma and ELF, and validate optimal dosing regimens for CAP using an integrated experimental and translational PBPK/PD framework.
Methods
A multi-stage translational modeling workflow was implemented using PK-Sim® and MoBi® v12.0.
Preclinical Modeling: A murine PBPK model was developed using plasma, lung tissue, and ELF data from SPF female ICR mice receiving 80 mg/kg subcutaneous nemonoxacin. In vitro transporter screening was conducted to identify active transport mechanisms of nemonoxacin, revealing P-gp-mediated efflux from lung intracellular fluid to the ELF, which was mathematically characterized using Michaelis-Menten kinetics.
Clinical Translation: The model was scaled to humans by integrating clinical data from three trials involving 1,082 plasma samples and 185 bronchopulmonary tissue samples (including bronchial mucosa, cartilage, and secretions).
PD Modeling and Target Determination: A semi-mechanistic PD model was established using in vitro time-kill data for two S. pneumoniae strains (SQ14 and SQ1). This model was linked to the PBPK framework to simulate bacterial growth-killing curves. In silico dose simulations (0–1000 mg once daily) were performed to derive PK/PD targets (AUC/MIC, $C_{max}$/MIC, and %T>MIC) for a 2-log₁₀ reduction in bacterial burden.
Dosing Optimization: Probability of target attainment (PTA) was calculated to evaluate the efficacy of the standard 500 mg once-daily oral regimen against various MIC values.
Results
The developed PBPK model successfully described nemonoxacin concentrations across human pulmonary compartments, with the majority of simulated values falling within a two-fold error of observed clinical data.
Translational analysis showed significant species differences in pulmonary penetration; the ELF-to-plasma AUCinf ratio in humans was 10.53, substantially higher than the 1.40 observed in mice. This was attributed to higher accumulation in human lung tissues (lung-to-plasma AUCinf ratio of 7.64).
For both S. pneumoniae strains, AUC/MIC was the PK/PD index best correlated with antibacterial effect in the ELF (R2 > 0.98). To achieve a 2-log₁₀ reduction in bacterial burden in the ELF, the required targets were an AUC/MIC of 18.95 in the ELF and a corresponding free plasma fAUC/MIC of 1.55. These values are notably lower than previously reported plasma-centric targets (e.g. fAUC/MIC of 44.4–93.7), suggesting that lower systemic exposures are sufficient for pulmonary clearance due to high site-of-infection accumulation. PTA analysis demonstrated that an oral dose of 500 mg once daily achieves >90% target attainment for isolates with MICs up to 16 mg/L.
Conclusions
This study establishes a robust translational PBPK/PD framework that accurately links systemic PK to site-specific antibacterial effects. The high penetration of nemonoxacin into human ELF justifies the clinical efficacy of the 500 mg once-daily regimen for S. pneumoniae-associated CAP. By determining targets for both ELF and plasma, this research provides a practical methodology for dose optimization in respiratory infections, especially when direct site-of-infection sampling is clinically challenging.
Reference:
1. Wu X, et al. Antimicrob Agents Chemother. 2015;59(3):1446-54.
2. Guo B, et al. Clin Drug Investig. 2012;32(7):475-86.
3. Nielsen EI, et al. Antimicrob Agents Chemother. 2011;55(10):4619-30.
4. Li X, et al. Front Pharmacol. 2021;12:658558.
5. Chen Y, et al. Front Pharmacol. 2023;14:912962.

Reference: PAGE 34 (2026) Abstr 12167 [www.page-meeting.org/?abstract=12167]

Poster: Drug/Disease Modelling - Other Topics