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Pharmacokinetics of sequential doses of capreomycin powder for inhalation in guinea pigs.
Antimicrob Agents Chemother. 2012 May; 56(5):2612-8.AA

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.

Authors+Show Affiliations

Division of Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22330920

Citation

Garcia-Contreras, L, et al. "Pharmacokinetics of Sequential Doses of Capreomycin Powder for Inhalation in Guinea Pigs." Antimicrobial Agents and Chemotherapy, vol. 56, no. 5, 2012, pp. 2612-8.
Garcia-Contreras L, Muttil P, Fallon JK, et al. Pharmacokinetics of sequential doses of capreomycin powder for inhalation in guinea pigs. Antimicrob Agents Chemother. 2012;56(5):2612-8.
Garcia-Contreras, L., Muttil, P., Fallon, J. K., Kabadi, M., Gerety, R., & Hickey, A. J. (2012). Pharmacokinetics of sequential doses of capreomycin powder for inhalation in guinea pigs. Antimicrobial Agents and Chemotherapy, 56(5), 2612-8. https://doi.org/10.1128/AAC.06145-11
Garcia-Contreras L, et al. Pharmacokinetics of Sequential Doses of Capreomycin Powder for Inhalation in Guinea Pigs. Antimicrob Agents Chemother. 2012;56(5):2612-8. PubMed PMID: 22330920.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetics of sequential doses of capreomycin powder for inhalation in guinea pigs. AU - Garcia-Contreras,L, AU - Muttil,Pavan, AU - Fallon,John K, AU - Kabadi,Mohan, AU - Gerety,Robert, AU - Hickey,Anthony J, Y1 - 2012/02/13/ PY - 2012/2/15/entrez PY - 2012/2/15/pubmed PY - 2012/8/18/medline SP - 2612 EP - 8 JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 56 IS - 5 N2 - 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. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/22330920/Pharmacokinetics_of_sequential_doses_of_capreomycin_powder_for_inhalation_in_guinea_pigs_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=22330920 DB - PRIME DP - Unbound Medicine ER -