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Intracellular concentrations of isoniazid and rifabutin resulting from administration of inhalable microparticles of these drugs to phorbol-differentiated THP-1 cells and the pharmacokinetics and biodistribution of these drugs upon inhalation of microparticles or intravenous administration of free drugs to mice were investigated. In cultured cells, both microparticles and dissolved drugs established peak concentrations of isoniazid (ϳ1.4 and 1.1 g/10 6 cells) and rifabutin (ϳ2 g/ml and ϳ1.4 g/10 6 cells) within 10 min. Microparticles maintained the intracellular concentration of isoniazid for 24 h and rifabutin for 96 h, whereas dissolved drugs did not. The following pharmacokinetic parameters were calculated using WinNonlin from samples obtained after inhalation using an in-house apparatus (figures in parentheses refer to parameters obtained after intravenous administration of an equivalent amount, i.e., 100 g of either drug, to parallel groups): isoniazid, serum half-life (t 1/2 ) ‫؍‬ 18. 63 h ؊1 ), and CL ‫؍‬ 11.68 ؎ 7.00 ml ⅐ h ؊1 (1.03 ؎ 0.11 ml ⅐ h ؊1 ). Drug targeting to the lungs in general and alveolar macrophages in particular was observed. It was concluded that inhaled microparticles can reduce dose frequency and improve the pharmacologic index of the drug combination.Several species of the genus Mycobacterium have evolved to survive in lung macrophages of the mammalian host, leading to granulomatous or latent tuberculosis (TB) (27). Chemotherapeutic regimens for TB require prolonged administration of multiple drugs through the oral route, but their ability to provide a lasting cure has not yet been established (7). We (18,21,29,30,38; H. Sen, J. Suryakumar, R. Sinha, R. Sharma, and P. Muttil, 3 September 2003, PCT patent application PCT/ IB2003/004694) and others (19, 23-26, 39, 40) have investigated several aspects of respirable or inhalable microparticles for treatment of pulmonary TB, first proposed by Hickey et al. (22,33,34). Particles developed by our group contain equal amounts of isoniazid and rifabutin and are meant for "adjunct therapy" of pulmonary TB through uptake by alveolar macrophages harboring Mycobacterium tuberculosis and/or related species. It is also speculated that, following uptake of microparticles, uninfected macrophages could traffic to lung areas where infected cells congregate. It has been demonstrated in animal experiments that inhaled microparticles target the drug payload to alveolar macrophages (21, 30) and enhance the efficacy of the incorporated agents (33, 34; Sen et al., PCT patent application PCT/IB2003/004694).The biopharmaceutics of both isoniazid (15,35,36) and rifabutin (3,4,31,32), both in humans and mice, are well known, and good correlations between the two species in terms of both kinetic data and therapeutic outcome have been observed (1).This report addresses the single-dose pharmacokinetics of isoniazid and rifabutin in polylactide microparticles administered by dry-powder inhalation to mice. Khuller et al. have extensively investigated the steady-s...

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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 high-performance liquid chromatography (HPLC). The RFB/INH in the lungs (101.10 ± 12.90/101.07 ± 8.09 μg/g of tissue) was 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 the operation of flip-flop kinetics. Thus, the elimination half-life (t(1/2)) of RFB and INH was calculated as 8.01 ± 0.5 and 2.49 ± 0.23 h, respectively, upon intravenous (iv) administration, and as 13.8 ± 0.8 and 10.43 ± 0.77 h following a single inhalation; or 13.36 ± 3.51 and 10.13 ± 3.01 at a presumed steady state (day 60 of dosing). Targeted and sustained drug delivery to nonhuman primate lungs and alveolar macrophages was demonstrated. Flip-flop serum pharmacokinetics was observed, and nonlinearity in some pharmacokinetic parameters at logarithmic dose increments was indicated. The results suggest that human patients would benefit through improvement in biodistribution following DPI.