Pharmacokinetics of Sequential Doses of Capreomycin Powder for Inhalation in Guinea Pigs

Abstract

The global control of tuberculosis (TB) is at risk by the spread of multidrug-resistant TB (MDR TB). Treatment of MDR TB is lengthy and involves injected drugs, such as capreomycin, that have severe side effects. It was previously reported that a single daily dose of inhaled capreomycin had a positive effect on the bacterial burden of TB-infected guinea pigs. The modest effect observed was possibly due to a dose that resulted in insufficient time of exposure to therapeutic systemic and local levels of the drug. In order to determine the length of time that systemic and local drug concentrations are above therapeutic levels during the treatment period, the present study investigated the disposition of capreomycin powders after sequential pulmonary administration of doses of 20 mg/kg of body weight. Capreomycin concentrations in bronchoalveolar lavage fluid and lung tissue of animals receiving a series of one, two, or three doses of capreomycin inhalable powder were significantly higher (50-to 100-fold) at all time points than plasma concentrations at the same time points or those observed in animals receiving capreomycin solution by intramuscular (i.m.) injection (10-to 100-fold higher). Notably, at the end of each dosing period, capreomycin concentrations in the lungs were approximately 100-fold higher than those in plasma and severalfold higher than the MIC, suggesting that sufficient capreomycin remains in the lung environment to kill Mycobacterium tuberculosis. No accumulation of capreomycin powder was detected in the lungs after 3 pulmonary doses. These results indicate that the systemic disposition of capreomycin after inhalation is the same as when injected i.m. with the advantage that higher drug concentrations are present at all times in the lungs, the primary site of infection. Multidrug-resistant tuberculosis (MDR TB) is an increasing challenge for the treatment and control programs of TB, a global deadly disease. Inappropriate treatment regimens with "first-line" drugs (mainly isoniazid and rifampin) and poor patient adherence to treatment have led to the increase in the number of MDR TB cases and, lately, the emergence of extensively drug-resistant cases (XDR TB) (8). Current international guidelines for the treatment of MDR TB recommend a treatment course of at least 18 months of "second-line" agents, including at least one of the following: capreomycin, ethionamide, kanamycin, or amikacin (22). With the exception of ethionamide, all these are administered by injection. These agents are more toxic, than generally not well tolerated, and less effective than first-line agents (19). While MDR TB is difficult to cure, XDR TB is often fatal; therefore, the judicious use of second-line drugs must be ensured to cure MDR TB or decrease its transmission and prevent emergence of XDR TB. Despite new drugs being evaluated, the present situation requires action to improve existing drug efficacy, delivery strategies, and mechanisms that support patient adherence to the prescribed treatment (11).The major limiting...

Phase I, Single-Dose, Dose-Escalating Study of Inhaled Dry Powder Capreomycin: a New Approach to Therapy of Drug-Resistant Tuberculosis

“…This represents only 60% of the apparent systemic half-life observed in the current study after single-dose pulmonary inhalation. In the guinea pig model, inhaled drug delivery also resulted in higher concentrations in the lung tissue and greater systemic mean residence times than when administered parenterally (21,27). This finding in an animal model provides evidence that inhaled capreomycin is superior to parenterally administered capreomycin in terms of achieving therapeutic pulmonary drug concentrations.…”

“…Eight hours after administration of a 20-mg/kg inhaled dose, lung tissue drug concentrations averaged 100 g/g tissue and far exceeded the concentrations achieved by the i.m. route of administration (27). In the multiple-dose portion of these studies, the AUC, half-life, and lung concentrations were higher and longer-lasting after the second and third doses (27).…”

“…dose (24). After a single 20-mg/kg inhaled dose, lung tissue homogenate concentrations reached 40 to 100 times the MIC for M. tuberculosis, while bronchoalveolar lavage fluid concentrations reached 40 to 50 times the MIC (27). Eight hours after administration of a 20-mg/kg inhaled dose, lung tissue drug concentrations averaged 100 g/g tissue and far exceeded the concentrations achieved by the i.m.…”

“…route of administration (27). In the multiple-dose portion of these studies, the AUC, half-life, and lung concentrations were higher and longer-lasting after the second and third doses (27). In addition, daily administration of the inhaled drug over 4 weeks (at 14.5 mg/kg) resulted in significant reductions in bacterial counts and lung pathology in M. tuberculosis-infected guinea pigs and the effect was greater than the pharmacodynamic effect on bacterial counts in the lung seen with the i.m.…”

Inhaled Pyrazinoic Acid Esters for the Treatment of Tuberculosis

“…Consequently, aerosol delivery of TB drugs could reduce the time of current therapies and/or more effectively treat latent TB, in which Mtb is encased in multicellular, poorly vascularized, and calcified granulomas that hinder drug penetration with oral therapy (31). Doses of aerosolized drug achieved in the lungs may be as much as two orders of magnitude higher than seen for the same dose delivered by other routes of administration (32). An additional benefit of inhaled therapy is that high systemic concentrations can be largely avoided, which reduces the potential for toxic side effects as occurs with several TB drugs.…”