The impurities of capreomycin make a difference in the safety and pharmacokinetic profiles

The emergence of multidrug-resistant tuberculosis (MDR-TB) has led to a renewed interest in the use of second-line antibiotic agents. Unfortunately, there are currently dearths of information, data, and computational models that can be used to help design rational regimens for administration of these drugs. To help fill this knowledge gap, an exploratory physiologically based pharmacokinetic (PBPK) model, supported by targeted experimental data, was developed to predict the absorption, distribution, metabolism, and excretion (ADME) of the second-line agent capreomycin, a cyclic peptide antibiotic often grouped with the aminoglycoside antibiotics. To account for interindividual variability, Bayesian inference and Monte Carlo methods were used for model calibration, validation, and testing. Along with the predictive PBPK model, the first for an antituberculosis agent, this study provides estimates of various key pharmacokinetic parameter distributions and supports a hypothesized mechanism for capreomycin transport into the kidney.

Section: Discussionmentioning

confidence: 99%

A Physiologically Based Pharmacokinetic Model for Capreomycin

Reisfeld

Metzler

Lyons

et al. 2012

“…PK parameters after administration of capreomycin solutions or suspensions have been determined predominantly for mice and humans (3,8,14,16,(19)(20)(21)28). There are no reports of these studies for guinea pigs, a species known to have a different drug disposition from that of other rodents.…”

Section: Discussionmentioning

confidence: 99%

Inhaled Large Porous Particles of Capreomycin for Treatment of Tuberculosis in a Guinea Pig Model

García-Contreras

Fiegel

Telko

et al. 2007

131

Capreomycin is used for the treatment of multidrug-resistant tuberculosis (MDR-TB), but it is limited therapeutically by its severe side effects. The objectives of the present studies were (i) to design low-density porous capreomycin sulfate particles for efficient pulmonary delivery to improve local and systemic drug bioavailability and capacity to reduce the bacillary load in the lungs in a manner similar to that achieved with intramuscular injections; (ii) to determine pharmacokinetic parameters after pulmonary administration of these capreomycin particles; and (iii) to evaluate the efficacy of these particles in treating animals in a small-aerosol-inoculum guinea pig model of TB. Capreomycin particles were manufactured by spray drying and characterized in terms of size and drug content. Pharmacokinetic parameters were determined by noncompartmental methods with healthy guinea pigs after administration of capreomycin particles by insufflation. The efficacy of the particles was evaluated by histopathological analysis and in terms of wet organ weight and bacterial burden in TB-infected animals. Lungs of animals receiving a 14.5-mg/kg dose of capreomycin particles showed significantly lower wet weights and smaller bacterial burdens than those of animals receiving any other treatment. These results were supported by histopathological analysis. The feasibility of inhaling capreomycin in a novel powder form, with the ultimate objective of the treatment of MDR-TB, is demonstrated by pharmacokinetic and pharmacodynamic studies with guinea pigs. If applied to humans with MDR-TB, such a therapeutic approach might simplify drug delivery by eliminating injections and might reduce adverse effects through lowering the dose.Worldwide, there is an increase in multiple drug-resistant tuberculosis (MDR-TB), including reports of outbreaks of extensive MDR-TB in several countries (4, 36). Patients suffering from MDR-TB have infections which are resistant to at least two key drugs in the first-line regimen, namely, rifampin and isoniazid, in part as a consequence of poor compliance to the current first-line regimen (approximately 23% of active TB patients presently complete first-line treatment) (5). To treat MDR-TB, other, second-line antibiotics are needed and therapy lasts up to 2 years, typically requiring parenteral injection (2).Among the drugs injected is the polypeptide antibiotic capreomycin, the only second-line drug specifically indicated for MDR-TB. Capreomycin is a complex of four microbiologically active components that has been shown to be effective in combination with other appropriate anti-TB drugs in the treatment of pulmonary Mycobacterium tuberculosis infections when the primary agents (in particular isoniazid and rifampin) have become ineffective as a result of bacterial resistance or toxicity. The drug is painful to receive by injection and is associated with serious side effects, such as anorexia, thirst, anemia, and notably, nephrotoxicity and damage to the auditory and vestibular divisions of cranial nerv...

“…routes and of solid particles delivered by the pulmonary route in guinea pigs (5). Pharmacokinetic (PK) parameters after administration of capreomycin solutions or suspensions have been determined in only mice and humans (2,3,7,9,(14)(15)(16)20), and there are no reports of these studies in guinea pigs, a species known to have drug disposition characteristics that are different from those of other rodents. Our study showed that capreomycin plasma concentrations were comparable in animals receiving capreomycin by the systemic and pulmonary routes after 2 h of drug administration (5).…”

mentioning

confidence: 99%

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

García-Contreras

Muttil

Fallon

et al. 2012

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...