Pharmacokinetic Evaluation and Tolerability of Dry Powder Tobramycin Via the Cyclops® in Children With Cystic Fibrosis

Rationale: Cystic fibrosis is the most common life-shortening autosomal recessive disease among Caucasian populations. It is a chronic progressive disease causing deterioration of pulmonary function, and of general condition as well. Although it is a multisystem disease, the primary cause of death is respiratory failure, resulting from chronic pulmonary infection.

Pseudomonas aeruginosa is the predominant pathogen. The presence of P. aeruginosa in patients with CF is an unfavourable prognostic indicator and is associated with accelerated lung tissue destruction and loss of lung function, subsequently leading tot increased morbidity and mortality. Preventing, limiting and treating chronic infection with P. aeruginosa is therefore crucial in the management of CF, to improve survival and quality of life.

Currently most children with CF who are colonized with P. aeruginosa receive inhaled tobramycin every other month, mostly by use of a nebulizer. This delivery system however has several disadvantages. For example, the nebulisation itself and the cleaning of the nebulizer is time consuming. This places a high burden on a CF patient, especially for children, which will negatively influence compliance and quality of inhalation, thereby jeopardizing effective treatment. Therapy with a (disposable) dry powder inhaler (DPI) is less time consuming. Besides this, nebulisation brings the risk of auto-re-infection of the patient (contamination of nebulisation fluid and/or device). Other more technical disadvantages of nebulisation are a low lung deposition and pollution with tobramycin in the surrounding environment. With an efficient DPI, a three to six fold higher lung deposition compared to a nebulizer can be obtained. Nebulised tobramycin is used most in routine care, but sometimes a DPI is used, for example the Podhaler®. Although the dispersion behaviour of these dry powder systems is often good, the engineering processes make the products expensive, and the high excipient fractions make the inhaled powder doses high. Furthermore because these devices are not disposable, there is a risk of bacterial resistance development in the device. Next to this is the hygroscopic nature of tobramycin a risk for good dispersion when a used DPI is store inappropriately. In this situation powder residues in the inhaler become sticky or even liquefied when they absorb moisture from the air. There is one disposable DPI for tobramycin available, called the Cyclops®, but this DPI is not registered for children with CF yet. The investigators will therefore investigate dry powder tobramycin (DP tobramycin) in the Cyclops® in children with CF.

Objective: The main objectives are to investigate the pharmacokinetic properties of DP tobramycin via the Cyclops® at different dosages in children with CF, together with the local tolerability.

Study design: Single center, single ascending, single dose study.