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IN VITRO EFFICACY AND IN VIVO SAFETY OF INHALED NANOPARTICLES OF TACROLIMUS

University of Texas Health Science Center, San Antonio, TX

PURPOSE: First: To establish in vitro efficacy of 2 cryogenically created nanoparticles of tacrolimus (TAC:LAC,TAC:URF) compared to commercial tacrolimus (PRO). Second: Determine the feasibility of nebulized nanoparticles of tacrolimus in a rodent model of lung transplantation by measuring lung concentrations of TAC:LAC and assessing histology after single/multidose administration.

METHODS: Mixed leukocyte culture (MLC) and mitogen stimulation assays (MSA) were used to tests the ability of TAC:LAC,TAC:URF, and PRO in reducing lymphocyte incorporation of radioactive thymidine. Four wells of modified RPMI (37 degrees in 5% PCO2) had 100µL of responder lymphocytes mixed with 100µL of pooled, irradiated allogenic cells. Equal concentrations of drug were added to all but control wells (.5 ng/ml-MLC;.23ng/ml-MSA). Four sets of responder lymphocytes were run in triplicate for each drug. After incubation, radioactive thymidine was added to each well and counts taken and compared to controls. TAC:LAC(respirable fraction/MMAD = 74.6%/2.6µm)was then nebulized in a mouse model (n=4) at a 10mg/ml concentration for 10 minutes/day in both single and multidose (7-14 day) studies. Lung levels of tacrolimus and histology were assessed.

RESULTS: MLC demonstrated that all 3 preparations suppressed lymphocyte proliferation versus controls. Inhibition in MLC assays was: PRO 38.5%%,TAC:LAC 54.5%,TAC:URF 65%. Inhibition in MSA was: Pro 40%,TAC:LAC 60%, TAC:URF 71%. Single dose TAC:LAC lung levels (Cmax) were 14.1 ± 1.50 µg/g; T of 20.02 hours,and an AUC = 122.42 ug.hr/gram. Steady state trough drug levels were 7.2µg/g at day 7 and 6.7µg/g at day 14. No inflammation or tissue damage were observed on histologic exam.

CONCLUSION: Nanoparticles of tacrolimus showed greater inhibition of lymphocytes than PRO when assessed by MLC and MSA. Nebulized TAC:LAC resulted in high peak and steady state trough levels within the lung. Histologic exam after 14 days of nebulized TAC:LAC suggests pulmonary dosing is safe.

CLINICAL IMPLICATIONS: Nanoparticulate formulations show promise for treating lung transplant recipients and patients with immune mediated pulmonary diseases by reducing the need for large doses of oral immunosupressants,localizing the drug to the site of intended action, and improving bioavailability.

DISCLOSURE: Jay Peters, None.