The Endothelial and Epithelial space implies the endosomal space in these compartments and accounts for FcRn mediated transcytosis and endosomal uptake through micropinocytosis (

The Endothelial and Epithelial space implies the endosomal space in these compartments and accounts for FcRn mediated transcytosis and endosomal uptake through micropinocytosis (. of endogenous IgG and albumin. The proposed framework can be used to assess pharmacokinetics of new lung-targeting biologic therapies and guide their dosing to achieve desired exposure at the pulmonary site-of-action. Keywords:Physiologically-based pharmacokinetics, Protein therapeutics, Pulmonary disposition, Lungs, Nasal PK, Monoclonal antibodies, Epithelial lining fluid, Alveolar space == Introduction == The incidence of lung disorders has been on the rise since the past couple of decades. A majority of the respiratory diseases observed today can be attributed to tobacco smoke, indoor or outdoor air pollution, and genetics [1]. In the United States, in 1980 the risk of death due to chronic respiratory illness was about 41 deaths per 100,000 people. Since then, it has risen to about 53 deaths per 100,000 people in 2014, almost a 31% rise in death risk due to respiratory issues. The Forum of International Respiratory Societies has released a report, identifying asthma, chronic obstructive pulmonary disease (COPD), acute respiratory infections, tuberculosis, and lung cancer as the top contributor to the global burden of respiratory diseases [2]; to which infectious diseases from common cold, influeza, tuberculosis and Covid-19 can be added too. About 65 million Epipregnanolone people suffer from COPD. The disorder kills 3 million people every year, making it the third leading cause of death worldwide. The CDC has estimated the Epipregnanolone total expenditure from 2011 to 2015 on treatment of Asthma and COPD was about $7 billion and $5 billion dollars, respectively [3]. Thus, pulmonary disorder is a major therapeutics area with intense research going on in the field. In the past 25 years, the use of protein therapeutics has been rising steadily, with approximately one third of all drugs approved by the FDA being biologics such as monoclonal antibodies. As macromolecules have large interaction surfaces, they can display high-affinity Epipregnanolone binding and hence are uniquely suitable for competing with endogenous proteinprotein interactions, albeit in extracellular space only. Unlike small molecule drugs, their breakdown products are naturally occurring amino acids which pose no toxicity risks, although pharmacological adverse effects remain a possibility [4]. The benefits provided by protein therapeutics outweigh the risks and a number of new drugs to treat pulmonary diseases, including COVID-19 have been biologics. Lung delivery of biologics can be achieved through systemic or pulmonary dosing. Systemic intravenous or subcutaneous dosing is well established but involves delay before the drug reaches lung and alveolar space, with only a small fraction of the drug eventually reaching that space at concentration that is substantially lower than in plasma [5]. Inhalation, on the other hand, affords instant, frequent and high exposure throughout the respiratory tract, but faces distinct challenges of its own. The bioavailability of the pulmonary dose, Bmp2 as well as relative distribution along the respiratory tract, depend on the formulation, principally the size of the particle or droplet. In the case of solids or aerosol droplets with diameter in the range of 15 m, as typical for nebulizers [6], around 7080% of dose is retained overall but only about a third of that is deposited in the alveolar space [7]. The absorbed protein initially encounters the epithelial lining fluid (ELF), which is a thin layer of liquid of complex composition containing high levels of proteoglycans and surfactant proteins among others [8]. This is followed by the competing processes of size-dependent absorption into systemic circulation and non-specific degradation in situ. As a result, the systemic bioavailability for the locally administered dose declines from close to 100% for small molecules to almost 0% for large proteins like albumin and IgG. In the case of insulin, 1020% bioavailability is accomplished following non-specific alveolar degradation with half-life around two hours [9,10]. In addition, pulmonary administration of several other proteins such as Epo-Fc, INF- etc. is actively being explored for systemic delivery [11,12]. Despite the potential advantages, most of the approved new inhaled medicines have been small Epipregnanolone molecules over the past decades, with only a small number being biologics [13], which reflects the challenges involved in successful systemic delivery of proteins following pulmonary administration. In order to facilitate the development of biologics for pulmonary disorders, following local or systemic administration, it is important to understand all the processes responsible for the disposition of biologics in the lung. Mathematical models that can describe the pharmacokinetics of biologics in the lung provide an opportunity to accomplish this goal in a thorough and quantitative manner. A number of compartmental, semi-mechanistic and physiologically-based pharmacokinetic (PBPK) models have been published in the past to describe pulmonary PK of small molecule drugs [1417]. However, such models are lacking for biologics. Here we propose a novel model to describe the PK of protein therapeutics in the lung, based on the PBPK framework, which.