Chapter 13 - Inhaled Biotherapeutics and Systemic Delivery

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13.1 Inhaled Interferon Gamma by Gerald C. Smaldone, MD, PhD

The pathway to impaired lung function and death in many pulmonary diseases frequently involves imbalances in immunity. The failure to control bacteria in tuberculosis is an example of a failed response to an antigen. Idiopathic Pulmonary Fibrosis (IPF) a progressive autoimmune fibrotic lung disease that can lead to respiratory failure and death within three years of diagnosis. Chronic obstructive pulmonary disease (COPD), often triggered by smoke, progresses until death and in recent years has also been labeled ”autoimmune.” Proposed mechanistic pathways of pathophysiology involve profibrotic cytokines unresponsive to usual anti-inflammatory agents (e.g. corticosteroids). Interferon-γ (IFN-γ) is a cytokine that can stimulate macrophage function and inhibit fibrotic pathways and therefore has been tried as therapy in tuberculosis and IPF. Unfortunately, for IPF, in several major clinical trials, parenteral IFN-γ failed to stem disease progression. Dosing in systemic therapy is limited by side effects. In recent studies, our group has approached this problem using inhaled IFN-γ targeted directly to the lung. In a controlled clinical trial, inhaled IFN-γ was effective in tuberculosis while parenteral IFN-γ was not, indicating that macrophages can be effectively immune-stimulated by aerosol therapy. We are taking a similar approach in IPF. We speculate that the same fibrotic pathways active in lung parenchyma may be at fault in the airways of COPD. These concepts suggest that clinical trials of inhaled IFN-γ are warranted.

13.2 Aerosol Delivery of Lung Surfactants by Ralph Niven

Exogenous lung surfactant is presently administered via intratracheal instillation for the treatment of infants at risk of or exhibiting signs of respiratory distress syndrome. Strong evidence from animal studies suggests that surfactant should be beneficial in a range of pulmonary conditions including acute respiratory distress syndrome, chronic obstructive pulmonary disease, pulmonary fibrosis and asthma. The utility of surfactant would be extended with the availability of an aerosol dosage form. In pre-term infants this may reduce the need for intubation and treatment with “rescue” surfactant while for adults, the option of efficient delivery systems in both critical care and ambulatory settings would be welcomed. Despite the promise of aerosol surfactant therapy, the results of human studies have been of mixed outcome and very few studies have been adequately controlled. Confounding the issue is a less than clear understanding of the dose received by patients, and in general, development and characterization of delivery systems has been inadequate. Thus, study outcomes may not reflect the potential of aerosolized surfactant. Factors impacting results differ for the patient population of interest. Designing an efficient delivery system in neonates is complex and is hampered by their rapid, shallow breathing maneuvers and their general fragility. In adults, depending on the setting, the complexity of the disease state may undermine any positive benefit that might otherwise exist and the present cost of therapy dampens the enthusiasm for the aerosol route of administration. Promise exists with artificial surfactants that can be produced at a large scale in a cost-effective manner but significant challenges must be addressed related to viscosity, composition and aerosol generator before the expected benefits of aerosolized surfactant can be realized.

13.3 Inhaled Chemotherapy by Janakiraman Subramanian, MD, MPH and Rajiv Dhand, MD, FACP, FCCP, FAARC

Cytotoxic chemotherapy remains the cornerstone of treatment for patients diagnosed with advanced stage cancers and is an important component in the multi-disciplinary treatment of several early stage cancers. In the majority of patients with cancer, cytotoxic chemotherapy is administered intravenously and in some instances by oral administration. Systemic administration of cytotoxic chemotherapy is well known to cause adverse effects, which can be severe and debilitating. Regional therapy with cytotoxic agents has the potential to reduce the extent of systemic exposure to the drug and reduce the risk of systemic adverse effects. Regional chemotherapy has been successfully employed in the treatment of certain solid tumors such as hepatocellular carcinoma. However, regional chemotherapy has not been commonly utilized for treatment of lung tumors. Inhaled cytotoxic chemotherapy has the potential to become an effective regional therapy for both primary lung cancer and metastases to the lung from other primary tumors. Aerosol administration of chemotherapy could potentially avoid some of the adverse effects seen with systemic therapy. In addition, some chemotherapeutic agents when administered as an aerosol are absorbed directly into the arterial circulation and have therapeutic effects at extrapulmonary sites. Aerosol administration of several different chemotherapeutic agents is currently under evaluation either in the preclinical setting or in early phase human trials. Some of these studies have shown that inhaled chemotherapy is feasible and effective in treating lung tumors. In this chapter, we review the published studies and ongoing trials on inhaled chemotherapy to better understand the current status of this field of cancer treatment.

13.5 Aerosol Delivery to the Nasal Cavity– A Tortuous Pathway to Efficacy by Maureen D. Donovan, PhD, Arthur (M-Y) Foo, PhD, and Namita Sawant

Aerosol delivery to the nasal cavity is quite different from delivery to the pulmonary system. The nasal airways are narrow and tortuous, and they provide a myriad of opportunities for particle deposition, yet directing that deposition to the desired site remains a challenge. A sudden narrowing of the airways in the nasal valve region, along with an accompanying airway direction change, results in the impaction of most aerosols immediately posterior to the nostril opening rather than within the main nasal cavity. While smaller-sized particles can traverse through the nasal valve and reach the main nasal cavity, their small size also allows them to pass entirely through the nasal cavity and enter the lungs, significantly limiting the use of < 5 μm particles for nasal delivery. The nasal cavity is compatible with a variety of formulation excipients, resulting in the opportunity to develop formulation/device combinations that exhibit specific, optimized characteristics for improved deposition and therapeutic efficacy. However, user-based variations in nasal cavity morphology and in administration technique place additional limitations on the efficient and reproducible delivery of nasal aerosols. A number of in vitro nasal airway model systems have been developed to assist in the identification of the factors controlling nasal deposition, and medical imaging techniques have also contributed to the understanding of nasal deposition patterns. Newer computational fluid dynamic modeling approaches have begun to provide more discrete and detailed information about nasal deposition, and these models offer the expanded opportunity to simulate deposition patterns using a variety of user-specific conditions or pathologies. The delivery of materials into the nasal cavity for optimal therapeutic effect remains challenging, and both an improved understanding of aerosol dynamics within the nasal airways and improved device technologies will be needed to fully utilize the potential of this delivery site.

13.6 Preclinical Safety by Ronald K. Wolff, PhD and James D. Blanchard, PhD

Several inhaled proteins and peptides have been developed to treat indications in the respiratory tract or systemically with varying degrees of success. This section will summarize the preclinical and clinical studies for inhaled Pulmozyme® (recombinant human deoxyribonuclease, rhDNase), insulin, human growth hormone (hGH), cyclosporine, alpha-1 antitrypsin, measles vaccine, and anti-immunoglobulin E (IgE). For Pulmozyme® (rhDNase), monkeys had positive serum antibody titers to rhDNase and allergic/ hypersensitivity (type I) lung lesions in response to foreign protein likely due to differences in homology between monkey and human DNases. However, in patients, the levels of rhDNase antibodies were low and of no consequence. For inhaled insulin in rats, dogs and monkeys, there were no adverse effects related to insulin or excipients. In clinical trials, over 13,000 patients were safely treated with inhaled insulin for an average of 1 year. Some patients had higher antibody levels than comparators, but these antibodies did not decrease the effectiveness, safety or tolerability of inhaled insulin over time and/or affect clinical outcomes. Inhaled hGH had no adverse effects in monkeys, healthy volunteers or pediatric patients, but its absorption from the lungs was too low (< 5%) in pediatric patients to be successful as a medical product. Inhaled cyclosporine had no unexpected systemic toxicity or clinically limiting findings in the respiratory tract in rat and dogs; it also had promising Phase 2 clinical data but failed in Phase 3. Inhaled alpha-1 antitrypsin also failed in a recent Phase 2/3 trial. A liquid inhaled measles vaccine was safe, well tolerated and produced an appropriate immune response in Phase 2/3 studies for children ages 10-35 months, but not younger. A dry powder inhaled vaccine in monkeys had no adverse effects and produced an immune response; Phase 1 trials are underway. Inhaled anti-IgE was well tolerated in monkeys and asthma patients, but systemic delivery had superior results in patients.

Keywords: biologics, biological products, biologicals, pharmacokinetics, chemotherapyAerosol, nebulizer, tuberculosis, pulmonary fibrosis, COPD, Lung, surfactant, aerosol, Respiratory Distress Syndrome, Lung cancer, nonsmall cell lung cancer, chemotherapy, lung metastasis, aerosol targeting, regional treatment, side effects, Nasal valve, nasal deposition, spray cone, spray angle, computational fluid dynamics, modeling, Inhalation, proteins, peptides, Pulmozyme®, rhDNase, insulin, growth hormone, cyclosporine, alpha-1 antitrypsin, measles vaccines, anti-IgE,