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Pharmacokinetics

Following aerosol administration of 14C-labeled doxorubicin in dogs, levels of radioactivity achieved in the lungs with aerosol delivery were higher, seemed to persist for longer period of time, and produced significantly lower systemic radioactivity levels than those observed after IV administration (Sharma et al. 2001). Similarly, liquid chromatography identified higher concentrations and slower clearance of paclitaxel from lung tissue extracts in dogs treated with inhaled liposomal paclitaxel versus IV administration of the same drug (Koshkina et al. 2001).

Cisplatin administered by an INC to the right caudal lung lobe of healthy dogs produced high platinum concentrations in the lung parenchyma (Selting et al. 2008). Immediately following a single inhaled dose, mean platinum levels in the lung were 44 times greater than in most other tissues, and peak blood levels were 15.6 times lower than those observed after IV infusion of a comparable dose. Later studies with inhaled liposomal cisplatin corroborated these findings (Chou et al. 2013).

Kelsen et al. reported that serum levels of cisplatin 5 min after an IV dose of 100-120 mg/m2, the dose commonly employed for treatment of osteosarcoma, ranged from 1600 to 9500 ng/mL (median 5500 ng/mL), (Kelsen et al. 1985). After 24 h of IV dosing, the serum cisplatin levels ranged from 400 to 3500 ng/mL (median 1400 ng/mL) (Kelsen et al. 1985). In contrast, following inhalation of cisplatin, serum levels after 30 min ranged from 43.6 to 157.4 ng/mL (median 84.6 ng/mL) and at 18-24 h postdose, the levels were 47.0-153.5 ng/mL (median 81.9 ng/mL) (Chou et al. 2013). As expected, cisplatin levels in the lung after inhalation were much higher than those achieved after IV administration of cisplatin. In 3 patients who had bronchoalveolar lavage (BAL) performed within 24 h of receiving inhaled lipid cisplatin, the levels in BAL (9.4, 2,951.9, and 11,201.6 ng/mL) tended to be variable but generally higher than the corresponding levels in serum (61.9, 50.2, and 80.4 ng/mL) (Chou et al. 2013). Similarly, 24 and 96 h after instillation of cisplatin conjugated with hyaluronan into the lungs of rats, platinum levels in the lung were 5.7 and 1.2-fold higher, respectively, compared to rats receiving IV cisplatin (Xie et al. 2010). The levels of platinum in the draining lymph nodes were higher and plasma platinum levels were more sustained with a reduced peak plasma concentration after instillation compared to IV administration; however, the animals developed patchy areas of moderate inflammation after instillation, suggesting that aerosolization may be preferable to instillation for delivering such cisplatin conjugates to the lung (Xie et al. 2010).

 
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