Structure-Based Prediction of Anti-infective Drug Concentrations in the Human Lung Epithelial Lining Fluid

Abstract

Purpose Obtaining pharmacologically relevant exposure levels of antibiotics in the epithelial lining fluid (ELF) is of critical importance to ensure optimal treatment of lung infections. Our objectives were to develop a model for the prediction of the ELF-plasma concentration ratio (EPR) of antibiotics based on their chemical structure descriptors (CSDs). Methods EPR data was obtained by aggregating ELF and plasma concentrations from historical clinical studies investigating antibiotics and associated agents. An elastic net regularized regression model was used to predict EPRs based on a large number of CSDs. The model was tuned using leave-one-drug-out cross validation, and the predictions were further evaluated using a test dataset. Results EPR data of 56 unique compounds was included. A high degree of variability in EPRs both between-and within drugs was apparent. No trends related to study design or pharmacokinetic factors could be identified. The model predicted 80% of the within-drug variability (R 2 WDV ) and 78.6% of drugs were within 3-fold difference from the observations. Key CSDs were related to molecular size and lipophilicity. When predicting EPRs for a test dataset the R 2 WDV was 75%. Conclusions This model is of relevance to inform dose selection and optimization during antibiotic drug development of agents targeting lung infections.

Intrapulmonary Pharmacokinetics of Relebactam, a Novel β-Lactamase Inhibitor, Dosed in Combination with Imipenem-Cilastatin in Healthy Subjects

“…The primary limitation of this study (as opposed to the general limitations of ELF studies) is that it was conducted in healthy volunteers, and there is limited information available regarding the correlation of pulmonary drug penetration in healthy volunteers to that in critically ill patients. Though they are limited, current data indicate that the lung penetration ratios observed in healthy volunteers appears to be directionally and often quantitatively similar to the penetration ratios observed in patients ( 31 ). Furthermore, the conduct of such a study in healthy subjects is common practice ( 32 ), due to feasibility considerations as well as the semiquantitative interpretability of study results ( 21 ).…”

Pooled population pharmacokinetic model of imipenem in plasma and the lung epithelial lining fluid

“…The treatment of lung infections due to common extracellular invading respiratory pathogens is one such important therapeutic application area, where the epithelial lining fluid (ELF) is the relevant site of infection. Antibiotic concentrations in the ELF indicative of drug penetration can differ greatly from corresponding plasma concentrations [24,25].…”

Design principles of collateral sensitivity-based dosing strategies

“…We did not consider that more complex evolutionary mutational trajectories can occur with associated complex patters of changes in antibiotic sensitivity and MIC 47 , which are not easily definable to apply to antibiotic treatment in general. Other factors not considered include local antibiotic tissue concentrations 48,49 , pharmacokinetic drug-drug interactions or the contribution of the immune system. We expect that such factors will not affect the specific subpopulations studied in different ways and therefore will not have a great impact on the general findings derived in this analysis.…”