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

Marcel Hoppentocht, Onno W Akkerman, Paul Hagedoorn, Jan-Willem C Alffenaar, Tjip S van der Werf, Huib A M Kerstjens, Henderik W Frijlink, Anne H de Boer, Marcel Hoppentocht, Onno W Akkerman, Paul Hagedoorn, Jan-Willem C Alffenaar, Tjip S van der Werf, Huib A M Kerstjens, Henderik W Frijlink, Anne H de Boer

Abstract

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.

Conflict of interest statement

Competing Interests: The employer of M. Hoppentocht, Dr. A.H. de Boer, Prof. Dr. H.W. Frijlink and P. Hagedoorn receives royalty payments over the sales of the Novolizer®, Genuair®/Pressair® and Twincer™ dry powder inhalers. Prof. Dr. H.A.M. Kerstjens receives consultancy fees for his institution from: Novartis, Pfizer, Boehringer Ingelheim, Almirall, GlaxoSmithKline, Takeda, Chiesi, Protaffin, Nycomed and AstraZeneca. The other authors have no conflicts of interest to declare. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. CONSORT flow diagram tobra-02 study.
Fig 1. CONSORT flow diagram tobra-02 study.
Fig 2. Individual serum concentrations of tobramycin…
Fig 2. Individual serum concentrations of tobramycin following administration of a 30 (A), 60 (B), 120 (C) or 240 (D) mg dry powder tobramycin dose from the Cyclops.
Fig 3. The C max per milligram…
Fig 3. The Cmax per milligram delivered dose as function of the inhaled volume.

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