Using Tobra in the eFlow

Pediatr Pulmonol. 2011 Apr;46(4):401-8. doi: 10.1002/ppul.21376. Epub 2010 Dec 30.

Higher Tobramycin concentration and vibrating mesh technology can shorten antibiotic treatment time in cystic fibrosis.

Coates AL, Denk O, Leung K, Ribeiro N, Chan J, Green M, Martin S, Charron M, Edwardes M, Keller M.

Physiology and Experimental Medicine, Research Institute of Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. allan.coates@sickkids.ca.

Abstract

Poor adherence to recommended therapy in cystic fibrosis (CF) is often because of the time demands of therapy. Tobramycin (TOBI®, 300 mg at 60 mg/ml) inhaled from the PARI LC PLUS® nebulizer requires about 20 min. 

This study determined if equivalent levels of pulmonary deposition could be achieved in shorter time using 1.5 ml of 100 mg/ml tobramycin solution delivered by an investigational eFlow® nebulizer. 

Sixteen males with stable CF, 8 children and 8 adults, and an FEV(1)  > 45% predicted inhaled both preparations on two occasions with (99m) Tc-DTPA added to the tobramycin. Blood samples were taken for quantification of tobramycin in the serum. The PARI LC PLUS® delivered 45.4 (39.3-51.6), mean and 95% CI, mg to the lungs in 17.0 ± 2.5 min (mean ± SD) with serum levels of 1,089 ± 388 µg/L. 

The investigational eFlow® delivered 46.3(40.3-51.7) mg in 4.0 ± 1.0 min with blood levels of 909 ± 458 µg/L. Only the time of delivery was significantly different with P < 0.0001 (paired t-test). Tolerability of the treatment was comparable for both inhalation regimes, but the shorter treatment was preferred by all patients.

 These results demonstrate the possibility of delivering equivalent levels of tobramycin much faster into the lungs of CF patients when using eFlow®, a very efficient electronic nebulizer. Pediatr Pulmonol. 2011; 46:401-408. © 2010 Wiley-Liss, Inc.

Copyright © 2010 Wiley-Liss, Inc.

No hearing loss after repeated courses of tobramycin in cystic fibrosis patients.

Acta Otolaryngol. 2009 May 28:1-6. [Epub ahead of print]

Related Articles

No hearing loss after repeated courses of tobramycin in cystic fibrosis patients.

Scheenstra RJ, Heijerman HG, Zuur CL, Touw DJ, Rijntjes E.

Department of Otorhinolaryngology, Head and Neck Surgery, The Netherlands Cancer Institute, Amsterdam.

Conclusion: Our results indicate that repeated treatment courses with tobramycin 10 mg/kg (twice daily for 3 weeks) may be safely applied in cystic fibrosis (CF) patients with respect to ototoxicity. The risk of hearing loss in this patient group is less than expected, which could be explained by either unfavourable baseline audiometry or the use of unidentified protective medication, or both. However, due to large inter-individual variations, audiometry screening remains important with respect to the detection of individual outliers. Objectives: Tobramycin is frequently prescribed for CF patients. In this study, hearing loss due to cumulative tobramycin exposure in adult CF patients was investigated. Patients and methods: We retrospectively investigated 19 patients with both baseline and follow-up audiometry before and after repeated courses of intravenous tobramycin (10 mg/kg/day in twice daily administrations for 3 weeks). Pure tone audiometry was performed at 0.250-16 kHz. Results: After repeated courses of tobramycin (median 3, range 1-8), the mean increase per frequency was 2.1 dB (median 0.5 dB, SD 12.6) with large (inter-individual) variations (range -23.5 to 34.5 dB). The pure tone averages (PTA) at 1-2-4 kHz and 8-10-12 kHz increased 1.4 dBHL and 2.3 dBHL, respectively, but were neither statistically significant, nor correlated with the cumulative tobramycin exposure.

PMID: 19479457 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/pubmed/19479457?dopt=Abstract

Tobramycin Inhalation Powder (TIP) Improved Lung Function In Cystic Fibrosis (CF) Patients With Respiratory Pseudomonas Aeruginosa (Pa) Infection

Main Category: Cystic Fibrosis
Also Included In: Respiratory / Asthma; Infectious Diseases / Bacteria / Viruses
Article Date: 20 May 2009 - 6:00 PDT

In a Phase III study, TIP, an inhaled investigational formulation of tobramycin, improved lung function (as measured by FEV1) in cystic fibrosis patients with Pseudomonas aeruginosa (Pa) infection, compared to placebo. The data, presented today at the American Thoracic Society (ATS) 2009 International Conference in San Diego, also demonstrated, with respect to secondary endpoints, that TIP decreased sputum Pa density, hospitalization and other antibiotic use in these patients versus placebo.

TIP is currently in Phase III development for the management of CF patients with Pa infection. TIP, a dry-powder form of tobramycin, is delivered in approximately 4 to 6 minutes via a hand-held, portable, pocket-sized inhaler device, twice daily.

More than half of the people with CF have Pa infection, a respiratory condition caused by the Pa bacteria that settle into the thick mucus trapped in the airways. Pa is the most common cause of infection and lung damage in patients with CF.

"The daily treatment routine for patients with CF can take hours. The study findings presented at ATS are promising, as a new treatment option like TIP may allow people with CF an alternative for Pa management," said lead investigator Michael Konstan, MD, Professor and Director, The LeRoy W. Matthews Cystic Fibrosis Center, Rainbow Babies and Children's Hospital and Case Western Reserve University School of Medicine.

In a Phase III placebo-controlled study, patients with CF were administered treatment with TIP 112mg twice daily or matching placebo in a 1:1 ratio during Cycle 1 (28 days on and 28 days off treatment). This was followed by 2 cycles where all patients received TIP1c. The primary efficacy variable was relative change in forced expiratory volume in one second (FEV1) percent predicted from Day 1 to Day 28 (Cycle 1).

At 28 days, patients on TIP showed a significant improvement in FEV1 % predicted with an average improvement of 13% versus placebo (p=.0016). At the end of the first full cycle (Day 56), improvement over placebo in predicted lung function was maintained.

With respect to secondary endpoints, TIP reduced the mean sputum Pa density by 2.59 log10 colony forming units (CFU/mL), compared with 0.24 log10 for placebo. The proportion of patients requiring other antipseudomonal antibiotics was lower with TIP versus placebo (19.6% vs. 32.7%) and the mean duration of additional antipseudomonal antibiotic use was shorter (17 vs. 31.1 days, respectively) over the 56 days of Cycle 1. There were no respiratory-related hospitalizations for patients on TIP compared with 12.2% for patients receiving placebo (average duration of 12.3 days).

Adverse events were reported by 75.5% of placebo-treated and 50% of TIP-treated patients. The most commonly reported adverse events with placebo were cough, lung disorders and productive cough. With TIP, the most common adverse events were cough, lung disorders and sore throat. There were no major changes from baseline in vital signs, hematology, blood chemistry or urine protein. Audiology tests at selected sites indicated that there were no clinically meaningful decreases in hearing thresholds. None of the patients reported adverse events related to hearing.

"Novartis is working closely with respiratory researchers worldwide to develop medications to treat complex respiratory diseases with limited treatment options, including cystic fibrosis," said Robert K. Zeldin, MD, VP and US Medical Franchise Head of Respiratory and Dermatology, Novartis Pharmaceuticals Corporation. "We are pleased to report the findings of the TIP Phase III study, and we look forward to additional clinical data as we work towards regulatory filing."

Source
Novartis Pharmaceuticals Corporation

Tobramycin-induced aquagenic wrinkling of the palms in a patient with cystic fibrosis.

Funny - I just asked my CF doc less than 5 days ago why this happens to me so quickly when I go swimming!

Tobramycin-induced aquagenic wrinkling of the palms in a patient with cystic fibrosis.

from PubMed: cystic fibrosis by Ludgate MW, Patel D, Lamb S

Related Articles

Tobramycin-induced aquagenic wrinkling of the palms in a patient with cystic fibrosis.

Clin Exp Dermatol. 2009 May 5;

Authors: Ludgate MW, Patel D, Lamb S

Summary Aquagenic wrinkling of the palms (AWP) is a rare condition, defined clinically by the appearance or accentuation of an asymmetrical, translucent to white, papular eruption on the palms after immersion in water. It is associated with cystic fibrosis (CF), and approximately half of all reported cases occur in patients with documented CF. We report a case of AWP in a young woman with CF, where the AWP was related to treatment with the aminoglycoside antibiotic, tobramycin. Although the mechanism of AWP is unknown, influx of water across an osmotic gradient into eccrine ducts has been proposed. Aminoglycosides may affect AWP by blocking various cell surface channels and receptors, which may influence cell-volume regulation.

PMID: 19438544 [PubMed - as supplied by publisher]

PARI Pharma wins orphan drug designation for cystic fibrosis therapy

Published:12-May-2009

By Datamonitor staff writer

PARI Pharma, a division of PARI GmbH and a developer of aerosol therapies, has received an orphan drug designation from the European Commission based on a positive recommendation by the European Medicines Agency for inhaled PARI Tobramycin 100 delivered via a customized investigational eFlow nebulizer system.

This is reported to be the second orphan drug designation (ODD) that PARI Pharma has received for a product in its proprietary drug pipeline; the first ODD was granted for PARI's inhaled cyclosporine delivered via an eFlow technology device.

PARI Pharma said that it is currently in discussions with multinational pharmaceutical companies to evaluate the efficacy of PARI Tobramycin 100 in a Phase III clinical study and to ultimately make this next-generation treatment available to cystic fibrosis (CF) patients worldwide.

Martin Knoch, president of PARI Pharma, said: "In clinical trials, we have seen a reduction to one-fourth of the inhalation time for PARI Tobramycin 100 compared to TOBI. This is a significant improvement that relates directly to patients' quality of life and ease of use.

"We believe this will lead to increased adherence to the antibiotic therapy, which is a major challenge for patients with CF. The ODD acknowledges the therapeutic value that this delivery concept will offer to patients suffering from CF."

http://regulatoryaffairs.pharmaceutical-business-review.com/news/pari_pharma_wins_orphan_drug_designation_for_cystic_fibrosis_therapy_120509

Phase III trial initiated for Tobra in the eFlow

PARI Pharma GmbH received an Orphan Drug Designation (ODD) by the European Commission based on a positive recommendation by the EMEA for inhaled PARI Tobramycin 100 delivered via a customized Investigational eFlow Nebulizer System. This is the second ODD designation that PARI Pharma has received for a product in its proprietary drug pipeline; the first ODD was granted for PARI's inhaled cyclosporine delivered via an eFlow Technology device.

"In clinical trials, we have seen a reduction to one fourth of the inhalation time for PARI Tobramycin 100 compared to TOBI. This is a significant improvement that relates directly to patients' quality of life and ease of use. We believe this will lead to increased adherence to the antibiotic therapy, which is a major challenge for patients with cystic fibrosis. The ODD designation acknowledges the therapeutic value that this delivery concept will offer to patients suffering from cystic fibrosis," said Dr. Martin Knoch, President of PARI Pharma GmbH.

PARI Pharma is currently in discussions with multinational pharmaceutical companies to evaluate the efficacy of PARI Tobramycin 100 in a Phase III clinical study and to ultimately make this next-generation treatment available to CF patients worldwide.

The EMEA regulation on orphan medicinal products is designed to promote the development of drugs, which may provide significant benefit to patients suffering from rare diseases identified as "life-threatening or very serious." In addition to potential 10-year EU market exclusivity following marketing approval, orphan drug status provides regulatory assistance and helps accelerate the approval of a drug product via a centralized procedure at reduced regulatory fees.

PARI conducted a Phase I clinical trial as a randomized, open label, crossover, single-dose deposition study of PARI Tobramycin 100 in an Investigational eFlow Nebulizer System versus TOBI/LC PLUS in 16 cystic fibrosis patients, including 8 adults and 8 children. Tobramycin lung deposition for both applications was between 46mg and 47mg. Results from the study will be presented at the European Cystic Fibrosis Conference (ECFC) in June 2009.

In addition, a Phase II multicenter clinical trial (10 sites) assessed safety and tolerability of PARI Tobramycin 100 (150mg/1.5mL) administered via an Investigational eFlow Nebulizer System in comparison to TOBI (tobramycin 300mg/5mL) delivered via the PARI LC PLUS. 78 patients suffering from cystic fibrosis (36 adults and 42 children) inhaled the study medication for 28 days in a parallel study design.

While key deposition and safety thresholds were maintained, the marked difference was a reduction in the average inhalation time to 4 - 4 1/2 minutes for the PARI Tobramycin 100, down from 16 - 17 minutes for the TOBI therapy, a 73% reduction in treatment time. Results for both formulations show no difference in the ratio of peripheral to central lung deposition. Maximum tobramycin serum levels were below recommended safety thresholds for systemic and inhaled tobramycin applications. Although tobramycin sputum concentrations were slightly higher in the T100 cohort, plasma levels and adverse reaction rates were slightly, but not significantly, lower being regarded as desirable. It appears that, for a twice-daily treatment with PARI Tobramycin 100 delivered via an Investigational eFlow Nebulizer System, approximately 10+ hours of inhalation time per month can be saved compared to TOBI.

About PARI Tobramycin 100

PARI Tobramycin 100 is an investigational proprietary aqueous solution of 150mg tobramycin/1.5mL for inhalation delivery via an optimized Investigational eFlow Nebulizer System, both developed by PARI Pharma, as a potential treatment for patients suffering from bacterial infections caused by Pseudomonas aeruginosa. Patents on both the drug formulation and device were granted in Europe and several other countries. Low volume/high concentration drug products such as PARI Tobramycin 100 delivered using eFlow Technology have been shown to substantially shorten nebulized treatments and are believed to offer an improvement for patients. The volume reduction to 1.5 mL and high drug concentration of 100 mg/mL developed for delivery via a customized Investigational eFlow Nebulizer System (with about two-fold higher delivery efficiency compared to jet nebulizer systems) are prerequisites to offer such treatment advantages.

About the Investigational eFlow Nebulizer System and eFlow Technology

The Investigational eFlow Nebulizer System uses eFlow Technology to enable highly efficient aerosolization of liquid medications via a vibrating, perforated membrane that includes thousands of small holes that produce the aerosol mist. Compared to other nebulization technologies, eFlow Technology produces aerosols with a very high density of active drug, a precisely defined droplet size, and a high proportion of respirable droplets delivered in the shortest possible period of time. Combined with its silent mode of operation, small size (it fits in the palm of your hand), light weight, and battery use, products incorporating eFlow Technology reduce the burden of taking daily, inhaled treatments. The Investigational eFlow Nebulizer System and eFlow Technology are proprietary to PARI Pharma.

PARI Pharma partners with pharmaceutical companies to develop new or improved therapies with eFlow Technology and other advanced delivery platforms. Investigational eFlow Nebulizer Systems are optimized and customized per investigational drug product and are currently in clinical trials for cystic fibrosis, asthma, COPD, respiratory syncytial virus (RSV) infection, and treatments for lung transplant patients among other indications.

About PARI Pharma

PARI Pharma focuses on the development of aerosol delivery devices, drug formulations, and therapies. Based on PARI's 100-year history working with aerosols, PARI Pharma develops treatments for pulmonary and nasal administration optimized with advanced delivery technologies, such as eFlow Technology.

PARI Pharma provides comprehensive inhalation drug development, including nebulizer formulation development and optimization, analytics, aerosol characterization, clinical protocol development, and regulatory guidance, all in compliance with CMC/GCP guidelines. PARI Pharma has several clinical development programs ongoing, either partnered or on its own. PARI Pharma, a PARI Medical Holding company, is located in