Xiaonan Zhang, Feiyan Liu, Zeneng Cheng, Feifan Xie
Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
Objectives: Pneumonia stands as a significant contributor to global infection-related mortality. Primarily bacterial in origin, pneumonia necessitates antibiotic treatment as a cornerstone intervention. The timely, appropriate, and adequate administration of antibiotics is paramount to improving the survival of pneumonia patients. However, prevalent suboptimal antibiotic utilization has led to a concerning surge in bacterial resistance, severely limiting the availability of effective antibiotic options. Tigecycline, a glycylcycline antibiotic, has emerged as a common therapeutic choice for pneumonia patients with antibiotic-resistant bacterial infections. Some studies have delved into the distribution of tigecycline in the epithelial lining fluid (ELF) and alveolar cells (ACs) of the lungs, revealing variations in concentration across different lung compartments. These discrepancies may stem from alterations in lung physiological conditions in pneumonia patients. Given that lung exposure plays a pivotal role in determining the antibiotic efficacy of tigecycline against pneumonia, it is imperative to elucidate the mechanisms underlying the distinct distribution between ELF and ACs. Therefore, this study aimed to access how physiological conditions associated with pneumonia influence tigecycline exposure in the lungs, examining both the ELF and ACs, utilizing a physiologically-based pharmacokinetic (PBPK) modeling approach. The insights gained from this study could serve as a mechanistic foundation for optimizing tigecycline dosage regimens in pneumonia patients.
Methods: A PBPK model of tigecycline for healthy adults was initially developed, by integrating a permeability-limited lung model based in pulmonary anatomy and physiology. The lung model consisted of seven segments, each subdivided into four compartments, including pulmonary capillary blood, tissue mass, fluid (representing mucus and ELF), and alveolar air. The tissue mass compartment accounted for various lung cell types, including ACs. The healthy PBPK model was evaluated and optimized using clinical data and subsequently extended to represent pneumonia patients. Given the typically more acidic lung environment and/or increased permeability in pneumonia patients with bacterial infections, the pH of ELF and/or pulmonary mass and permeability parameters of lung were adjusted to reflect this diseased related condition. Simulations were conducted by modulating the pH of ELF and/or pulmonary mass and apparent permeability coefficient (Papp) of lung to assess changes in lung exposure of tigecycline within ELF and ACs. The model development and simulation were conducted using Simcyp population-based PBPK simulator (version 21).
Results: The developed tigecycline PBPK model demonstrated robust predictive accuracy in plasma, ELF, and ACs concentrations for healthy adults. Approximately 93.9% of the observed concentrations in plasma fell within the 2-fold range of the model mean predictions. The PBPK model for pneumonia patients demonstrated accurate prediction for patient plasma concentrations, with 91.7% of the observed concentrations falling within the 90% confidence interval of the model mean predictions. Our simulations elucidated increasing the Papp of pulmonary to 1.5 or 2 times the original value did not result in significant changes in the predicted concentration-time curves within ACs. Similarly, no discernible differences were observed in the predicted concentration-time curves of tigecycline within ELF and ACs when lowering the pH value in ELF from 6.7 to 6.0 or 5.6. However, notably, upon decreasing the pH value of pulmonary mass from 6.7 to 6.0 or 5.6, while only subtle reductions in the concentration-time curves of tigecycline were predicted within ELF, a significant increase in tigecycline exposure was observed within ACs, which was in line with data reported in previous studies.
Conclusions: The decrease in pH within pulmonary mass emerges as a significant determinant of alterations in tigecycline lung exposure among pneumonia patients. The developed tigecycline PBPK model offers valuable insights into the importance of considering lung-specific physiological conditions when optimizing tigecycline treatment regimens for pneumonia patients.
Reference: PAGE 32 (2024) Abstr 11190 [www.page-meeting.org/?abstract=11190]
Poster: Drug/Disease Modelling - Absorption & PBPK