Preclinical Safety Evaluation of Inhaled Cyclosporine in Propylene Glycol

Abstract

Cyclosporine inhalation solution has the potential to improve outcomes following lung transplantation by delivering high concentrations of an immunosuppressant directly to the allograft while minimizing systemic drug exposure and associated toxicity. The objective of these studies was to evaluate the potential toxicity of aerosolized cyclosporine formulated in propylene glycol when given by inhalation route to rats and dogs for 28 days. Sprague-Dawley rats received total inhaled doses of 0 (air), 0 (vehicle, propylene glycol), 7.4, 24.3, and 53.9 mg cyclosporine/kg/day. In a separate study, beagle dogs were exposed to 0, 4.4, 7.7, and 9.7 mg cyclosporine/kg/day. Endpoints used to evaluate potential toxicity of inhaled cyclosporine were clinical observations, body weight, food consumption, respiratory functions, toxicokinetics, and clinical/anatomic pathology. Daily administration of aerosolized cyclosporine did not result in observable accumulation of cyclosporine in blood or lung tissue. Toxicokinetic analysis from the rat study showed that the exposure of cyclosporine was approximately 18 times higher in the lung tissue compared to the blood. Systemic effects were consistent with those known for cyclosporine. There was no unexpected systemic toxicity or clinically limiting local respiratory toxicity associated with inhalation exposure to cyclosporine inhalation solution at exposures up to 2.7 times the maximum human exposure in either rats or dogs. There were no respiratory or systemic effects of high doses of propylene glycol relative to air controls. These preclinical studies demonstrate the safety of aerosolized cyclosporine in propylene glycol and support its continued clinical investigation in patients undergoing allogeneic lung transplantation.

Lung Deposition and Pharmacokinetics of Nebulized Cyclosporine in Lung Transplant Patients

“…(22) However, the high lung concentrations post aerosol administration will decline rapidly, unlike those in cell culture, and aerosol studies carried out in beagle dogs administered CIS three times per week for 9 months at dose levels up to 12 times higher per kilogram than those received by human patients, demonstrated no macroscopic or histopathological changes to lung tissue. (23) The observations of drug reaching the stomach raise the possibility that oral absorption may contribute to the blood concentration versus time profiles after inhalation. No charcoal block was given prior to dosing, and therefore oral uptake cannot be ruled out.…”

Electronic cigarettes: an aid in smoking cessation, or a new health hazard?

“…Propylene glycol (1,2 propanediol) is a diol (a polyhydric alcohol with a 2-hydroxyl group) that was discovered in 1859, 79 was recognized as safe for use in food products by the US FDA in 1982 80 and is also used in pharmaceuticals, including intravenous and inhalational preparations. 81 – 83 In the human body, it is mainly metabolized to lactate and then to pyruvate and glucose. Glycerol (1,2,3-propanetriol) is a polyol (a polyhydric alcohol with a 2-hydroxyl group) that exists in nature, is essential for living organisms, was first discovered in 1783 and has been approved for use in food products since 1959.…”

COUNTERPOINT: Does the Risk of Electronic Cigarettes Exceed Potential Benefits? No

“…Propylene glycol is present in several FDA-approved injectable medications, and aerosolized propylene glycol is being evaluated for delivery of inhaled medications. 7 In summary, although not everything is known about e-cigarette vapor, the available data support the notion that it is vastly less toxic than tobacco cigarette smoke.…”