Abstract:
Dry powder inhalations (DPI) of microparticles containing isoniazid (INH) and rifabutin (RFB) are under preclinical development for use in pulmonary tuberculosis. Microparticles containing 0.25, 2.5 or 25 mg of each drug were administered daily for 90 days to rhesus macaques (n=4/group). Single inhalations or intravenous (i.v.) doses were administered to separate groups. Drugs in serum, alveolar macrophages and organ homogenates were assayed by HPLC. RFB/INH in lungs (101.10 12.90 / 101.07 8.09 µg/g of tissue) were twice that of the liver concentrations (60.22 04.97 / 52.08 4.62 µg/g) and four times that of the kidneys (22.89 05.22 / 30.25 3.71 µg/g). Pharmacokinetic parameters indicated operation of flip-flop kinetics. Thus, elimination half-life (t½) of RFB and INH was calculated as 8.01 0.5 and 2.49 0.23 hr, respectively, upon i.v. administration, and as 13.8 0.8 and 10.43 0.77 hr following a single inhalation; or 13.36 3.51and 10.13 3.01 at presumed steady state (day 60 of dosing). Targeted and sustained drug delivery to non-human primate lungs and alveolar macrophages was demonstrated. Flip-flop serum pharmacokinetics were observed and non-linearity in some pharmacokinetic parameters at logarithmic dose increments was indicated. The results suggest that human patients would benefit through improvement in biodistribution following DPI.
