Tolerability and Pharmacokinetic Evaluation of Inhaled Dry Powder Tobramycin Free Base in Non-Cystic Fibrosis Bronchiectasis Patients

Rationale Bronchiectasis is a condition characterised by dilated and thick-walled bronchi. The presence of Pseudomonas aeruginosa in bronchiectasis is associated with a higher hospitalisation frequency and a reduced quality of life, requiring frequent and adequate treatment with antibiotics. Objectives To assess local tolerability and the pharmacokinetic parameters of inhaled excipient free dry powder tobramycin as free base administered with the Cyclops dry powder inhaler to participants with non-cystic fibrosis bronchiectasis. The free base and absence of excipients reduces the inhaled powder dose. Methods Eight participants in the study were trained in handling the device and inhaling correctly. During drug administration the inspiratory flow curve was recorded. Local tolerability was assessed by spirometry and recording adverse events. Serum samples were collected before, and 15, 30, 45, 60, 75, 90, 105, 120 min; 4, 8 and 12 h after inhalation. Results and Discussion Dry powder tobramycin base was well tolerated and mild tobramycin-related cough was reported only once. A good drug dose-serum concentration correlation was obtained. Relatively small inhaled volumes were computed from the recorded flow curves, resulting in presumably substantial deposition in the central airways-i.e., at the site of infection. Conclusions In this first study of inhaled dry powder tobramycin free base in non-cystic fibrosis bronchiectasis patients, the free base of tobramycin and the administration with the Cyclops dry powder device were well tolerated. Our data support further clinical studies to evaluate safety and efficacy of this compound in this population

Optimisation of the sensitivity of an immunoassay analysis for tobramycin in serum

Tobramycin is an aminoglycoside antimicrobial drug frequently used in anti-pseudomonal therapy in cystic fibrosis and non-cystic fibrosis bronchiectasis patients. Therapeutic drug monitoring is routinely performed to increase efficacy and reduce the chance of toxicity. The most frequently used method to quantify tobramycin in serum or plasma is with an immunoassay method. However, immunoassays lack sensitivity to evaluate the lower concentrations of tobramycin for pharmacokinetic studies of for instance inhaled tobramycin. The aim of this study was to optimise the Syva® Emit® 2000 Tobramycin Assay combined with the ARCHITECT c8000. This adapted method was validated for accuracy and precision, having within-run, between-run variation. The adapted tobramycin immunoassay method has a linear range of 0.03 to 0.6 mg/L, which is comparable to liquid chromatography-mass spectrometry methods. The immunoassay method was validated with representative samples and has been implemented in routine analysis

Dry powder inhalation of antibiotics: A promising approach for treatment of infectious diseases

In the thesis of Marcel Hoppentocht the feasibility to treat bacterial infections effectively with inhaled dry powder antibiotics is explored. Most antibiotics are currently administered pulmonary by wet nebulisation or via the parenteral route and both methods have numerous disadvantages. For instance, needle fear and the need for ‘cold chain storage’ of the drug solution are major drawbacks of parenteral administration. Nebulisation is time-consuming, it requires electricity or pressurised air and this, in addition to their size, makes nebulisers not very portable. Cleaning and disinfection of nebulisers burden patients particularly and this results in poor compliance with the instructions for use of their equipment and negatively affects the therapy. In the thesis, dry powder inhalation is presented as an alternative and current developments and strategies for inhaled dry powder antibiotics in tuberculosis therapy are critically evaluated in relation to the technological challenges, safety and practical needs. A new strategy is presented based on the philosophy to keep the inhaler simple and cheap, but safe and effective and for this approach new inhaler technology has been developed based on the Twincer® high dose, disposable inhaler with air classifier technology. Re-designing the basic Twincer® concept into a new device named Cyclops enabled effective delivery of aminoglycosides (tobramycin, amikacin and kanamycin) without using an excess of excipients and complex particle engineering techniques for the drug formulation. Promising results of a first patient study with the developed formulation-device combination are presented and they show the way to new and better treatments for bacterial infections

Inhalatie van droog poeder veelbelovend bij longinfectie: Pulmonale toediening antibiotica: snelle werking en minder bijwerkingen

Pulmonale toediening van antibiotica blijkt veelbelovend voor de behandeling van infectieuze longaandoeningen. Een snelle werking op de plaats waar het geneesmiddel nodig is en minder systemische bijwerkingen zijn belangrijke voordelen. De Twincer-familie van droogpoederinhalatoren biedt uitkomst voor hoge doseringen

In vitro evaluation of the Twincer colistin dry powder inhaler as a non-cough-inducing alternative to Colobreathe

Background: patients prefer dry powder inhalation to nebulisation but the Colobreathe dry powder inhaler for colistimethate sodium (CMS) is not well appreciated in the Netherlands for a number of different reasons, including serious cough problems by some patients after inhalation of the drug. Aim: to assess the suitability of the Twincer as alternative to the Colobreathe for patients having problems with this capsule based inhaler. Methods: in vitro evaluation of the Twincer (55 mg) and Colobreathe (125 mg) was performed using the Next Generation Impactor and a laser diffraction apparatus (Sympatec HELOS) operated at 4 kPa (inhalation volume: 4L; n = 3). Results: laser diffraction analyses shows a finer aerosol from the Twincer than from the Colobreathe. Delivered CMS doses and fine particle doses (FPFs 1-5 μm) from Colobreathe were 126 mg (+14.7/-31.9 mg) and 25.5 mg (+2.8/-3.5 mg) respectively versus 48.5 mg (+2.9/-3.3 mg) and 26.4 mg (+1.4/-1.2 mg) from Twincer. Capsule fragmentation and emission of capsule fragments was observed during evaluation of the Colobreathe but not for the Twincer (having the drug in an aluminum blister). Conclusions: The higher dispersion efficiency of the Twincer (FPF is 54.4% of delivered dose versus 20.2% for Colobreathe) enables to inhale a much lower dose (at lower flow rate) without capsule fragments in the aerosol. As a consequence, the Twincer is expected to be better tolerated by patients and, therefore, provides a suitable alternative to the Colobreathe. This expectation is corroborated by positive feedback from the first patients suffering from CF or non-CF bronchiectasis who received the Twincer on the basis of 'medical need'