Assessment of Epithelial Lining Fluid Partitioning of Systemically Administered Monoclonal Antibodies in Rats.

For systemically administered monoclonal antibodies (mAbs) with pharmacological targets in the epithelial lining fluid (ELF), information on the partitioning of mAb between plasma and ELF is instrumental for dose predictions. Bronchoalveolar lavage (BAL) combined with measurements of urea as indicator of sample dilution is often used to estimate ELF concentrations of a drug. However, unbalanced extraction of mAb and urea could potentially lead to a systematic bias in the back-calculated ELF concentration. In the present study 0.5, 1, or 4 mL phosphate-buffered saline was instilled to lungs of rats to obtain lavage samples after systemic dosing of mAb and tool small molecule (n≥4/group). Furthermore, extraction of urea, mAb and the small molecule was assessed by repeatedly lavaging the lung (n = 4). There was no statistically significant difference in the calculated partitioning into ELF between the evaluated instillation volumes. Repeated BAL demonstrated that urea and the small molecule were extracted from other sources than the ELF. In contrast, there was limited to none in-flow of mAb into the lavage fluid. The unbalanced extraction of urea and mAb could theoretically result in underestimated ELF concentrations and the calculated partitioning of 0.17±0.062 might therefore constitute a lower boundary for the true partitioning.

Possible Extraction of Drugs from Lung Tissue During Broncho-alveolar Lavage Suggest Uncertainty in the Procedure's Utility for Quantitative Assessment of Airway Drug Exposure.

Following inhaled dosing, broncho-alveolar lavage (BAL) is often used for sampling epithelial lining fluid (ELF) to determine drug concentration in the lungs. This study aimed to explore the technique's suitability. Urea is typically used to estimate the dilution factor between the BAL fluid and physiological ELF, since it readily permeates through all fluids in the body. As representatives of permeable small molecule drugs with high, medium and low tissue distribution properties, propranolol, diazepam, indomethacin and AZD4721 were infused intravenously to steady state to ensure equal unbound drug concentrations throughout the body. The results showed that propranolol had higher unbound concentrations in the ELF compared to the plasma whilst this was not the case for the other compounds. Experiments with different BAL volumes and repeated lavaging indicated that the amount of drug extracted is very sensitive to experimental procedure. In addition, the results show that the unbound concentrations in ELF compared to plasma differs dependent on molecule class and tissue distribution properties. Overall data suggests that lavaging can remove drug from lung tissue in addition to ELF and highlights significant uncertainty in the robustness of the procedure for determining ELF drug concentrations.