key: cord-0897005-j3uw09mx
authors: Drwiega, Emily N.; Rodvold, Keith A.
title: Authors’ Reply to De Sutter, De Waele, and Vermeulen: “Penetration of Antibacterial Agents into Pulmonary Epithelial Lining Fluid: An Update”
date: 2022-01-04
journal: Clin Pharmacokinet
DOI: 10.1007/s40262-021-01101-2
sha: e69f7b23c8be71c8707e823b2061f54d52cdd0a5
doc_id: 897005
cord_uid: j3uw09mx

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This sophisticated and potentially complex analysis is being employed by academic, regulatory, and industry investigators to address drug selection and system-specific development issues (e.g., study design, first-in-human dosing, various dosage formulations, drug-drug interactions, and pharmacokinetic variability) in different patient populations even when drug exposure data may be difficult to determine [7, 8] . Several recently published manuscripts have documented the usefulness of PBPK modeling to predict systemic and pulmonary ELF exposure of antibacterial agents, including drugs being repurposed for COVID-19 [9] [10] [11] [12] .

When we first started conducting intrapulmonary penetration studies almost 30 years ago, lung tissue homogenates and comparison with concomitant plasma concentrations were still being advocated [13, 14] . Since that time, the paradigm has shifted to measuring specific sites of where bacterial lung infections occur (i.e., extracellular and intracellular drug concentrations), assessing in vivo pharmacodynamics of antibacterial agents in animal infection models, and applying population pharmacokinetic-pharmacodynamic modeling and simulation for developing dosage regimens applicable to both research studies and/or clinical practice [2, 4, 5] . We acknowledge that measuring ELF concentrations and population-pharmacokinetic modeling are not a panacea for understanding intrapulmonary penetration of antibacterial agents and ensuring clinical success for the treatment of bacterial pneumonia. However, this current approach has advanced the importance of drug exposure in the lung and assisted in the dose selection of new (and old) antibacterial agents.

There is little doubt that the collection of site concentrations in critically ill patients is challenging and one of the major limitations of why there is limited ELF concentration-time data during drug development programs. Noninvasive techniques would surely improve the opportunities to collect lung concentrations to assist in the optimal design of dosage regimens for the treatment of critically ill patients with hospital-acquired and ventilator-associated bacterial pneumonia. The use of exhaled breath condensate has already been used for non-invasive evaluation of lung diseases [15] . The combination of exhaled breath condensate samples with nanobiosensor sensitive analytical techniques and/or endogenous dilution markers (i.e., urea) should improve quantification issues of antibacterial concentrations [16] [17] [18] . However, further validation of these techniques will be needed and comparison to other sample collection methods of assessing intrapulmonary drug concentrations should be considered. Using real-world exhaled breath condensate concentrations and clinical information to perform PBPK modeling will however be challenging, appealing for critically ill patients during (and after) the drug development program for antibacterial agents. We encourage these types of investigations for measuring intrapulmonary concentrations of anti-infective agents and pharmacokineticpharmacodynamic modeling options to improve the care of patients with lower respiratory tract infections.

Comment on: "Penetration of antibacterial agents into pulmonary epithelial lining fluid: an update

Penetration of antibacterial agents into pulmonary epithelial lining fluid: an update

Considerations for dose selection and clinical pharmacokinetics/pharmacodynamics for the development of antibacterial agents

Pharmacokinetic-pharmacodynamic considerations in the design of hospital-acquired or ventilator-associated bacterial pneumonia studies: look before you leap! Clin Infect Dis

Considerations for effect site pharmacokinetics to estimate drug exposure: concentrations of antibiotics in the lung

Penetration of anti-infective agents into pulmonary epithelial lining fluid: focus on antibacterial agents

Physiological based pharmacokinetic (PBPK) modeling and simulations: principles, methods, and applications in the pharmaceutical industry

Physiological based pharmacokinetic model qualification and reporting procedures for regulatory submissions: a consortium perspective

Towards a generic tool for prediction of meropenem systemic and infection-site exposure: a physiological based pharmacokinetic model for adult patients with pneumonia

Development of an adult physiologically based pharmacokinetic model of solithromycin in plasma and epithelial lining fluid

Impact of disease on plasma and lung exposure of chloroquine, hydroxychloroquine and azithromycin: application of PBPK modeling

Pharmacokinetics under the COVID-19 storm!

Penetration of clarithromycin into lung tissues from patients undergoing lung resection

Tissue concentrations: do we ever learn?

Exhaled breath condensate: an evolving tool for noninvasive evaluation of lung disease

Biosensor-enabled multiplexed on-site therapeutic drug monitoring of antibiotics

Personalized medicine for antibiotics: the role of nanobiosensors in therapeutic drug monitoring

Pharmacokinetics of intravenous and inhaled salbutamol and tobramycin: an exploratory study to investigate the potential of exhaled breath condensate as a matric for pharmacokinetic analysis