Pharmacokinetics of aerosolized tacrolimus in rats

Aims: The persistent airway connection to the environment offers a selective route of drug delivery for tracheal or lung grafts. This study aimed to investigate the pharmacokinetics of oral and aerolized tacrolimus in an orthotopic rat tracheal transplant model.

Methods: Sixty Lew recipients of orthotopic BN tracheal grafts were treated with either oral (4mg/kg) or aerosolized tacrolimus (4mg/kg). After 5 days, 6 rats per group were euthanized 0, 1, 3, 6 or 12 hours after drug administration. Blood was drawn and tracheas and lungs were harvested to quantify tacrolimus levels using HPLC.

Results: With oral tacrolimus, peak and trough blood levels of 67.1±12.0ng/ml and 6.0±0.7ng/ml were reached after 1 and 12 hours, respectively. Treatment with same-dose aerosolized tacrolimus resulted in considerably lower peak (7.2±1.0ng/ml) and trough levels (1.6±0.2ng/ml) with a 5.5-fold lower AUC0–12 (oral: 210±68ng/ml/h, aerosol: 38±12ng/ml/h; p<0.001). Interestingly, trachea tissue levels reached higher peaks in animals receiving aerosolized tacrolimus (901±175ng/g vs. 502±93ng/g; p<0.001). Thereafter, trachea tissue levels declined more rapidly in the aerosol group. Tracheal tissue level AUCs0–12, however, were similar after oral (3046±305ng/g/h) and inhaled (2693±284ng/g/h) treatment (p=0.065). Lung tissue levels were more elevated with oral tacrolimus (Cmax=580±85ng/g) than with the aerosol (Cmax=447±47ng/g) and tissue AUCs0–12 (oral: 3659±272ng/g/h, aerosol: 1666±237ng/g/h) were significantly higher (p<0.001).

Conclusions:

1) Aerosolized tacrolimus can be delivered to the airway graft,

2) similar AUCs0–12 can be achieved in the trachea with oral or inhaled drug administration,

3) systemic blood levels remain very low during inhalation therapy,

4) drug delivery to the upper airway is more effective than into the periphery.