Toxicity and Pharmacokinetic Studies of Aerosolized Clinical Grade Azacitidine

Abstract

Aerosolized clinical grade azacitidine (Aza) was tested for aerosol quality in vitro and pharmacokinetics and systemic and pulmonary toxicity in vivo in mice. The aerodynamic size range of the aerosol droplets favored the deposit of the drug to the human lower airways and the aerosol process did not compromise the drug activity. No significant myelosuppression, pulmonary toxicity, hepatotoxicity, or nephrotoxicity were observed at a daily dose of 2.5 mg/m2 (0.83 mg/kg) 7 days. Reversible lung inflammation was found in mice treated with aerosolized Aza at dose 3-fold higher than the anticipated therapeutic dose (7.5 mg/m2 or 2.5 mg/kg daily for 7 days) at 3 weeks after the treatment, but not after 6 weeks. In a single dose pharmacokinetic study, aerosolized Aza was found to deposit mainly into the lung with very little drug detected in the circulation. The area under the curve (AUC) of drug in the lung was more than 22-fold greater than that of the peripheral blood: the peak concentration (Cmax) was 7.42 µg/g in lung as compared to 0.28 µg/ml in blood. The total clearance was only 0.010/h in lung vs 0.22/h for blood. In contrast, intravenously (IV) injected Aza resulted in a high Aza concentration in the peripheral blood (Cmax = 4.94 µg/ml), with only trace amounts of drug in the lung (Cmax = 0.35 µg/g). IV Aza was associated with bone marrow toxicity, as it caused significant myelosuppression in the mice. Our results indicate that aerosolized Aza has much less systemic toxicity than IV administered drug and that a safe starting dose of aerosolized Aza for clinical phase I trials in humans should be 2.5 mg/m2 (0.83 mg/kg) daily for 5 to 7 days.

Acetylation and Methylation in Asthma, COPD, and Lung Cancer

“…Generally, azacitidine is administered by subcutaneous injections, leading to systemic exposure. However, localized delivery of the drug to the lungs by means of inhalation was proven highly effective in animal models, because it was associated with longer survival, less toxicity, and less lung cancer burden compared to subcutaneous injection [122]. The results of that study sparked the initiation of the phase I trial.…”