Pharmacokinetic and Toxicity Profile of a Phosphorothioate Oligonucleotide Following Inhalation Delivery to Lung in Mice

Abstract

Antisense oligonucleotides are currently being investigated for the treatment of a variety of diseases. Antisense drugs are being administered primarily by parenteral injection. To explore more convenient patient delivery methods, we have characterized the tissue kinetics and tolerability of an inhaled aerosol formulation of a phosphorothioate oligonucleotide in mice. Concentrations of oligonucleotide in bronchioalveolar lavage fluid, plasma, and tissue and immunohistochemical localization were used to assess deposition and pharmacokinetic parameters. Significant concentrations of oligonucleotide in lung, as well as systemic tissues, were measured following a pulmonary dose of 12 mg/kg. Doses as low as 1-3 mg/kg also produced significant concentrations of oligonucleotide (>50 microg oligonucleotide per gram of tissue), and these were maintained in the lung with a halflife of 20 hours or greater. Oligonucleotide was localized to bronchiolar epithelium and alveolar epithelium and endothelium. Toxicity was mild at the 12 mg/kg level and minimal to absent at doses of 3 mg/kg or below. Based on a favorable pharmacokinetic profile and a relative lack of toxicity, inhalation delivery appears to be a therapeutic option for antisense oligonucleotides.

Inhaled CD86 Antisense Oligonucleotide Suppresses Pulmonary Inflammation and Airway Hyper-Responsiveness in Allergic Mice

“…In Cynomolgous monkeys, after three administrations of aerosolized CD86 ASO via intubation directly into the airways at the top of the bronchial tree, 0.02% of the delivered dose was recovered in peribronchial lymph nodes and 0.2% was recovered in kidney, with no measurable oligonucleotide detected in liver. Immunohistochemical staining of oligonucleotide following either intratracheal instillation or aerosol inhalation revealed oligonucleotide distributed throughout the large and small airways and associated with alveolar macrophages and lung alveolar epithelium (Templin et al, 2000). An increase in the numbers of CD86ϩ DCs in the mediastinal lymph nodes was noted following successive OVA challenges.…”

The effect of in vitro exposure to antisense oligonucleotides on macrophage morphology and function

“…Local administration to the lung can be approached non-invasively by oral inhalation, using aerosolized ONs. Pulmonary bioavailability with concurrent low systemic levels has been reported using areosolized antisense oligonucleotides (AONs), [1][2] presenting the opportunity of treating local respiratory diseases with direct pulmonary doses and minimizing the exposure of non-target tissues. In addition, the large absorption surface area of the lung 1 and its lining with cationic lipid-containing surfactant has been proposed to facilitate AON uptake within the lungs.…”

“…It has been reported that repeated pulmonary administration of a PS AON on a subacute basis (e.g., 2 weeks) can lead to microscopic changes in the respiratory tract of rodents and monkeys. 2,9 The most common alterations observed can be categorized into two types of responses: i) a mononuclear cell infiltrate located within the pulmonary interstitium and other parenchymal regions; and ii) an accumulation of macrophages in the alveolar region [i.e., an increase in the number of alveolar macrophages (AMs)]. The former response (mononuclear cell infiltration) may be akin to the inflammation at sites of injection that is observed when ONs are given by other routes (as discussed above), 8 whereas the influx of AMs has been speculated to be non-inflammatory in nature and possibly more of a non-specific response to an inhaled foreign material, as such accumulation of AMs is often observed with inhalation of other substances.…”

A Multi-Targeted Antisense Oligonucleotide-Based Therapy Directed at Phosphodiesterases 4 and 7 for COPD

“…The pharmacokinetics properties following pulmonary delivery has been well characterized (Templin et al 2000;Ali et al 2001;Guimond et al 2008) and confers a significant advantage of AON over small molecule drugs. For example, orally-delivered Daxas/Daliresp has a bioavailabilty of 79% (David 2004) and with an elimination half-life of 14-18 h there is a greater opportunity for this drug to act upon PDE4 outside of the lung and for a long period of time.…”

“…Firstly, as PXS TPI1100 is administered via inhalation, it is delivered directly to the intended site of action of the lung (Ali et al 2001;Duan et al 2005;Gauvreau et al 2008;Guimond et al 2008) where the drug can enter target cells directly (Zhang et al 2004;Griesenbach et al 2006) thus potentially reducing total dose as compared to orally-available treatments. A further advantage of pulmonary administration of AON is that they are principally www.intechopen.com A Multi-Targeted Antisense Oligonucleoitde-Based Therapy Directed at Phosphodiesterases 4 and 7 for COPD 449 metabolized in the lung with very limited systemic delivery after inhalation (Templin et al 2000;Ali et al 2001;Guimond et al 2008) which leads to reduced systemic bioavailability of the drug. In comparison to Daxas/Daliresp, which is delivered orally and has a high level of bioavailability, the projected low systemic bioavailability of PXS TPI1100 may limit adverse events associated with PDE4 inhibitors, namely the gastrointestinal and neurological side effects.…”