(S-022) Dose Optimization of Inhaled Tigecycline in Humans to Overcome Inherent Adverse Events and Maximize Bacterial Clearance Using a PBPK Modeling Approach

Hyunseo Park – Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN; Amarinder Singh – Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN; Anthony Hickey – Technology Advancement and Commercialization, RTI International, Durham, NC; Sara Maloney – Technology Advancement and Commercialization, RTI International, Durham, NC; Mercedes Gonzalez-Juarrero – Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO; Bernd Meibohm – Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN

Objectives: Recently, pulmonary delivery (IPA) of tigecycline has been highlighted as an optimal strategy for enhancing local drug concentrations at the site of infection in the treatment of Mycobacterium abscessus (Mab) pulmonary infections. This approach is particularly effective in cystic fibrosis (CF) patients, a population highly vulnerable to Mab infections in terms of both prevalence and mortality. However, since pulmonary administration was not originally considered during tigecycline development, there are no established dosing guidelines for this route, and therapeutic experience remains limited to case studies. Despite the benefit of local delivery, excessive inhaled tigecycline can lead to increased systemic exposure, which could be associated with adverse events, particularly in gastrointestinal and bone proliferation systems. Therefore, determining an appropriate inhaled dosage is imperative to optimize therapeutic use of tigecycline.

Methods: In this study, we aimed human translation by leveraging various preclinical experimental datasets through physiologically-based pharmacokinetic (PBPK) modeling. Using model-based simulations, we predicted the longitudinal exposure profiles of tigecycline in the systemic circulation, the epithelial lining fluid (ELF) in the lungs as site of antibacterial activity, and other major organs following inhalation under clinically relevant conditions.

Results: IPA dosing at the currently approved IV dosing regimen was predicted to result in significantly lower plasma systemic exposure at steady state compared to the adverse event (AE) threshold reported in the literature (6.87 mg·h/L). Additionally, simulated steady-state bone concentrations remained below a threshold of 1 mg/L, which was defined as the steady-state bone trough concentration leading to toxicity in rats. For efficacy, IPA administration produced markedly higher peak concentrations in ELF, and the simulated exposure in ELF (〖AUC〗_(0-24.ss)^ELF) exceeded levels identified in in vivo animal models. Our findings indicate that, compared to conventional intravenous infusion, inhaled tigecycline not only offers an improved safety margin but also enhances bacterial killing potential.

Conclusions: Based on simulation results for multiple scenarios, we proposed 135 mg Q3D as an optimized potential dosing regimen that balances both efficacy and safety. The optimized inhaled dosing regimen proposed in this study is expected to serve as a valuable guideline for treating Mab-mediated pulmonary infections in CF patients, ultimately aiming at improving therapeutic success rates and reducing mortality.

Citations: [1]] Pedersen AA, Floe A, Lokke A, Hilberg O. Pulmonary Mycobacterium abscessus infection treated in combination with inhaled tigecycline. BMJ Case Rep 16. (2023)
[2] Kwon YS, Levin A, Kasperbauer SH, Huitt GA, Daley CL. Efficacy and safety of tigecycline for Mycobacterium abscessus disease. Respir Med 158 89-91. (2019)

Keywords: PBPK, Human Dose Prediction, Inhalation