Tobramycin administered by the TOBI(®) Podhaler(®) for persons with cystic fibrosis: a review

Abstract

From its introduction, the antibiotic tobramycin has been an important tool in the management of persons with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa lung infections. Initially an intravenous rescue treatment for pulmonary exacerbations, tobramycin delivered by inhalation has become a mainstay of chronic suppressive CF infection management. Platforms for tobramycin aerosol delivery have steadily improved, with increased lung deposition complimented by decreased device complexities, loaded tobramycin doses, delivery times, and treatment burdens. Most recently, a unique tobramycin inhalation powder (TIP) formulation with a portable delivery system, the TOBI(®) Podhaler(®) (Novartis AG, Basel, Switzerland) has been developed and approved in Europe, Canada, and Chile. Four capsules, each containing 28 mg of TIP are successively pierced and inhaled via the T-326 Dry Powder Inhaler Device (Novartis AG, Basel, Switzerland). No external power source is required to deliver an efficacious tobramycin dose in minutes. By comparison, tobramycin inhalation solution (TIS) (TOBI(®); Novartis), is delivered by LC(®) Plus (PARI Respiratory Equipment Inc, Midlothian, VA) jet nebulizer powered by an air compressor over 15-20 minutes. Comparative pharmacokinetics, safety, and efficacy studies of TIS and TIP in CF subjects with P. aeruginosa ≥ 6 years old demonstrate that: tobramycin lung deposition with 112 mg TIP is comparable to that attained with 300 mg TIS, TIP is more effective than placebo and not inferior to TIS with respect to pulmonary function benefit, and TIP has significantly faster treatment times and achieves higher patient satisfaction than TIS. TIP is associated with an increased frequency of mild to moderate local adverse events (cough, dysphonia, and dysgeusia) compared with TIS, however, these become less frequent as subjects gain TIP experience. These results suggest that the TOBI Podhaler may better meet the needs of many CF patients and families by reducing treatment time and complexity and improving patient satisfaction compared with TIS.

Keywords: cystic fibrosis; dry powder inhaler; tobramycin.

Figure 1

Pulmonary function outcomes from randomized, controlled, blinded inhaled-tobramycin studies. (A) Comparison of TIS to placebo. (B) Comparison of TIP to placebo for 1 treatment cycle followed by two cycles of treatment with TIS. (C) Comparison of TIS to TIP for 3 treatment cycles. Notes: Gray circles, subjects randomized to receive 112 mg TIP twice daily; black circles, subjects randomized to receive 300 mg TIS twice daily; open circles, subjects randomized to receive matching placebo treatment twice daily; gray zones and solid lines, 28-day periods where subjects were receiving study treatments; dashed lines, 28-day periods where subjects were not receiving study treatments; bars represent 95% confidence intervals for means. A adapted with permission from Ramsey BW, Pepe MS, Quan JM, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med. 1999;340(1):23–30; © 1999 New England Journal of Medicine. B adapted with permission from Konstan MW, Geller DE, Minić P, Brockhaus F, Zhang J, Angyalosi G. Tobramycin inhalation powder for P. aeruginosa infection in cystic fibrosis: the EVOLVE trial. Pediatr Pulmonol. 2011;46(3):230–238. C adapted from Journal of Cystic Fibrosis, Vol 10, Issue 1, Michael W Konstan, Patrick A Flume, Matthias Kappler, Raphaël Chiron, Mark Higgins, Florian Brockhaus, Jie Zhang, Gerhild Angyalosi, Ellie He, David E Geller, Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: The EAGER trial, Pages 54–61, Copyright 2011, with permission from Elsevier.

Figure 2

TIP PulmoSpheres^® (Novartis AG, Basel, Switzerland) and the T-326 Dry Powder Inhaler Device (Novartis AG). (A) Electron micrograph of PulmoSpheres, which are light, hollow, porous, particles that are less dense than milled powders, and travel more slowly in the inspiratory airstream, thus avoiding impaction in the upper airways. (B) The T-326 inhaler is a simple, capsule-based dry powder inhaler that is portable, inexpensive, and disposable. Note: Adapted from J Aerosol Med Pulm Drug Deliv. 2011;24(4):175–182 with permission; the publisher for this copyrighted material is Mary Ann Liebert, Inc publishers.