Multidrug-resistant tuberculosis (MDR-TB) threatens global TB control. The lengthy treatment includes one of the
injectable drugs
kanamycin,
amikacin, and
capreomycin, usually for the first 6 months. These drugs have potentially serious toxicities, and when given as
intramuscular injections, dosing can be painful. Advances in particulate
drug delivery have led to the formulation of
capreomycin as the first antituberculosis
drug available as a microparticle dry
powder for inhalation and clinical study. Delivery by
aerosol may result in successful treatment with lower doses. Here we report a phase I, single-dose, dose-escalating study aimed at demonstrating safety and tolerability in healthy subjects and measuring pharmacokinetic (PK) parameters. Twenty healthy adults (n = 5 per group) were recruited to self-administer a single dose of inhaled dry
powder capreomycin (25-mg, 75-mg, 150-mg, or 300-mg nominal dose) using a simple, handheld delivery device. Inhalations were well tolerated by all subjects. The most common adverse event was mild to moderate transient
cough, in five subjects. There were no changes in lung function, audiometry, or laboratory parameters.
Capreomycin was rapidly absorbed after inhalation. Systemic concentrations were detected in each dose group within 20 min. Peak and mean plasma concentrations of
capreomycin were dose proportional. Serum concentrations exceeded 2 μg/ml (MIC for Mycobacterium tuberculosis) following the highest dose; the half-life (t1/2) was 4.8 ± 1.0 h. A novel inhaled microparticle dry
powder formulation of
capreomycin was well tolerated. A single 300-mg dose rapidly achieved serum
drug concentrations above the MIC for Mycobacterium tuberculosis, suggesting the potential of inhaled
therapy as part of an MDR-TB treatment regimen.