The PK/PD Core will provide 1) pharmacokinetic (PK) measurements of drug concentrations over time in airway surface liquid (ASL) from all three projects and 2) in-vivo pharmacodynamic (PD) measurements of mucociliary and cough clearance (MCC/CC) for the animal and human projects (Projects II and 111). 1. Pharmacokinetics. The pharmacological activities of drugs that affect mucus hydration are a reflection of their concentrations on airway surfaces. Measuring airway drug concentrations in human subjects is difficult using traditional methods. Bronchoscopic lavages suffer from variable dilutions and uncertainties about site sampled, and sputum likely reflects an abnormal secretion that originates primarily from large airway surfaces. Accordingly, we will develop mass spectrometric methods to accurately measure ASL concentrations of drugs, drug metabolites, and markers of ASL dilution that can be applied both to non-invasive airway samples such as exhaled breath condensate (EBC) and to other ASL samples obtained from all three projects. 2. Pharmacodynamics. Quantifying the response of mucociliary function to treatments targeted for chronic obstructive airways disease requires accurate, sensitive in-vivo measurements of MCC/CC for both animal and human models. Accordingly we will: a. Measure mucociliary clearance in mice by tracking tracheal velocities of fluorescently labeled beads for baseline and drug interventions that parallel those in the clinical projects. b. Measure MCC/CC in human subjects using techniques that standardize radiotracer deposition. Both baseline MCC/CC and the effects of mucolytic treatments will be assessed as described in Project 111. Measures of airways obstruction, ciliary dependent clearance (MCC), cough-dependent clearance (CC), and novel endpoints to describe heterogeneity of clearance will be made available to Project investigators. c. Engineer and produce novel particles of controlled size and shape for deposition on airway surfaces that 1) accurately track the movement of mucus from the lung and 2) permit multi-modal imaging (e.g. single photon emission computed tomography, positron emission tomography [PET], or MRI) to better delineate the degree and site of MCC abnormalities within the lungs of patients when combined with diagnostic imaging of lung structure (CT and MRI) and inflammation (PET).
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