Pulmonary drug delivery continues to be an exciting and evolving method for new pharmaceutical agents. Recent data has estimated that the global pulmonary drug delivery technologies market may reach US$37.7 billion by 2015.1 Aerosol-based formulations offer a number of advantages, including limited systemic side effect profile, alternatives to self-injections, and limited dependence on infusion delivery devices. Based on this need, the pharmaceutical industry is investing major resources in aerosol drug delivery and biotechnology, including research in particle engineering, dry powder formulations, protein and peptide-based therapeutics, dispersion technology, drug delivery methods, and drug delivery device design. This research is leading to a frontier of newer pharmacotherapeutic alternatives to be administered for aerosol delivery. These comprise antibiotics, antidiabetic agents, analgesics, antiemetics, nicotine replacement, hormone therapy, and vaccines. As pharmaceutical technology advances, the future of pulmonary drug delivery via aerosol will continue to represent another alternative delivery method for patients. The potential result of this new technology is improvement in health care-related outcomes, including decreasing disease-related patient morbidity and mortality.
Aerosol Aztreonam (Cayston®)
Aztreonam is a monobactam antibacterial antibiotic, which has been traditionally administered via the intravenous route for patients with infections involving Gram-negative pathogens including Pseudomonas aeruginosa, Haemophilus influenzae, Proteus mirabilis, and Escherichia coli. The drug is traditionally administered in adults as a 30-minute IV infusion every 8 to 12 hours.2 Based on its effectiveness for Gram-negative pathogens within the lungs and unique chemical structure, studies ensued to determine its effectiveness as an aerosol formulation. Gilead Sciences Inc (Foster City, Calif) received US Food and Drug Administration (FDA) approval in February 2010 for Cayston (aztreonam lysine for inhalation or AZLI). Aztreonam lysine for inhalation is indicated to improve respiratory symptoms in cystic fibrosis patients >7 years of age with P. aeruginosa infection in the lungs.3 Aztreonam lysine has been studied in multiple phase 2, phase 3 (AIR-CF1, AIR-CF2, and AIR-CF3), and phase 3b (AIR-CF4) studies. Results of the studies demonstrated that AZLI significantly improved respiratory symptoms, pulmonary function, and sputum P. aeruginosa density compared with placebo.4-7 When used after a course of tobramycin inhalation, it delayed the time to need intravenous antipseudomonal agents.5 Aztreonam lysine is a sterile lyophilized powder in a vial with a 1 ml ampule of sterile solvent. After both are reconstituted, the nebulizer solution contains 75 mg aztreonam lysine formulation. The drug is administered as 75 mg three times daily over a period of 28 days and is delivered via the Altera Nebulizer System®, which delivers the 75 mg dose over a period of 2 to 3 minutes.8-9 The minimum interval is 4 hours between doses, and the minimum AZLI free period between treatment courses is 28 days.3 This Altera Nebulizer System uses the eFlow® Technology Platform, developed by PARI Pharma GmbH. The eFlow technology is a vibrating perforated membrane with thousands of holes that produce the aerosol mist. The drug should be used only in the Altera Nebulizer System and should not be mixed with any other drugs in the nebulizer device. A short-acting bronchodilator is recommended before administering AZLI. The most frequent adverse effects (>10% of patients) include cough, wheezing, nasal congestion, or pharyngolaryngeal pain. Caution is advised in patients with a documented allergy to beta-lactam antibiotics, such as penicillins, cephalosporins, and/or carbapenems, since cross-reactivity may occur.
Dulera® (mometasone furoate/formoterol fumarate dihydrate)
Dulera is a combination inhaled corticosteroid (mometasone furoate) with a long-acting beta2-agonist (formoterol fumarate dihydrate). Merck Pharmaceuticals (Whitehouse Station, NJ) received FDA approval in the United States in June 2010 for mometasone furoate/formoterol fumarate dihydrate (MF/F).10 Mometasone furoate/formoterol fumarate dihydrate is a new fixed-dose combination asthma treatment for patients 12 years of age or older. A 26-week placebo-controlled trial evaluated 781 patients 12 years of age and older comparing MF/F 100 µg/5 µg (n=191 patients), mometasone furoate 100 µg (n=192 patients), formoterol fumarate 5 µg (n=202 patients), and placebo (n=196 patients), each administered as two inhalations twice daily by MDI. Mometasone furoate/formoterol fumarate dihydrate 100 µg/5 µg demonstrated significant improvement in FEV1 from baseline to week 12 compared to placebo (0.13 L vs -0.05 L, P < 0.001). Secondary endpoints also demonstrated improvements in nocturnal awakenings (-60% vs -15%), change in total rescue medication use (-0.6% vs +1.1 puffs/day), change in morning peak flow (+18.1 vs -28.4 L/min), and change in evening peak flow (+10.8 vs -32.1 L/min) of MF/F compared to placebo.11 In a 12-week, randomized, multicenter, double-blind, parallel-group study, patients >12 years of age were randomized to MF/F 200 µg/10 µg, MF/F 400 µg/10 µg, or MF 400 µg twice daily after a 2- to 3-week open-label run-in with MF 400 µg twice daily; 728 were randomized. Significant improvement in baseline to week 12 occurred in FEV1 with MF/F 400 µg/10 µg versus MF 400 µg (4.19 L/hr vs 2.04 L/hr; P < 0.001). Both MF/F doses were superior to MF in improving asthma control and decreasing nocturnal awakenings due to asthma requiring short-acting beta agonist use.12 Mometasone furoate/formoterol fumarate dihydrate is available in two strengths: 100 µg/5 µg and 200 µg/5 µg. It is supplied as a pressurized aluminum canister. The canister is equipped with a dose counter that will display “124” actuations at purchase. Before initiating the first dose, the patient should proceed with initial priming with four actuations, the dose counter will read “120,” and the inhaler is now ready for use. A “black box” warning is included in the package insert that warns of asthma-related deaths associated with long-acting beta2 adrenergic agonists (LABA), such as formoterol, one of the active ingredients of MF/F.11 Although data has identified that MF/F is safe and well tolerated in patients with persistent asthma, other adverse effects that may occur include adrenal suppression, decreased bone mineral density, and immunosuppression.
Insulin (Exubera® and Afrezza®)
Insulin is one of many pharmaceutical agents to maintain glycemic control for diabetic patients. Diabetes is considered one of the fastest-growing disease entities in the United States, encompassing 23.6 million people (17.9 million diagnosed and 5.7 million undiagnosed) who represent 7.8% of the US population.13 Subcutaneous insulin injections and various classes of oral antidiabetic agents have been the two primary delivery methods for treatment of hyperglycemia in type 1 and type 2 diabetes mellitus. New advances in aerosol delivery have developed inhaled formulations to assist in glycemic control and to provide another therapeutic delivery method for patients. In February 2006, Pfizer Pharmaceuticals (Collegeville, Pa) in conjunction with Nektar Therapeutics (San Carlos, Calif) received FDA approval for their inhaled insulin product Exubera.14 Exubera was considered to be a potential blockbuster drug, with projections of US sales greater than $1 billion. Unfortunately, approximately 2 years after approval and dismal sales, Pfizer withdrew Exubera from the US market. Although the drug demonstrated efficacy in assisting in glycemic control, withdrawal was based on a number of factors, including patients requiring periodic pulmonary function testing due to potential pulmonary complications of the inhaled product, cumbersome apparatus that was not designed for portable transport, concern over lung cancer associated with its use, and losing US$2.8 billion in development costs.14-15 Although removal of Exubera was a major setback for the use of inhaled insulin, there is hope for another inhaled insulin product.
MannKind failed to win US approval for its first product, Afrezza (insulin human [rDNA origin]), an inhaled insulin for diabetes. The FDA wants the company to do two new studies of the device in patients with Type 1 and Type 2 diabetes. This action will delay the drug from coming on the market by 18 to 24 months, according to CEO Alfred Mann.
MannKind Pharmaceuticals (Valencia, Calif) completed phase 3 trials in 2009 and submitted a new drug application (NDA) to the FDA in May 2009 for the drug Afrezza (insulin human [rDNA origin]) inhalation powder.15 Insulin human (rDNA origin) is indicated for use in adult patients with type 1 and type 2 diabetes mellitus for the treatment of hyperglycemia. The drug was headed for FDA approval, when, in March 2010, the FDA asked for more information on the phase 3 trial as well as the delivery device.16 This agent has many advantages of Exubera, including a premetered, light, discreet delivery device. Further, peak insulin levels are achieved within 12 to 14 minutes after administration. Some experts estimate that insulin human (rDNA origin) will receive FDA approval in early 2011.
Aminoglycoside antibiotics (amikacin, tobramycin, and gentamicin) are primarily indicated for the treatment of serious Gram-negative organisms such as P. aeruginosa and Serratia and Proteus species, and Gram-positive infections such as Staphylococcus aureus, including methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA), and Enterococcus species. These agents are traditionally administered via the IV route in conjunction with other antibiotics for treatment of multiple types of infections, including pneumonia, endocarditis, and bacteremia. Aminoglycosides administered via the IV route exhibit poor lung penetration and, thus, require careful monitoring of peak and trough serum levels to maintain efficacy and monitor toxicity (nephrotoxicity and ototoxicity). This class of antibiotics was the first to receive FDA approval in 1998 as an aerosol agent, tobramycin (TOBI®). Inhaled tobramycin was approved for the management of cystic fibrosis patients with P. aeruginosa infection.17 Based on the success of inhaled tobramycin, other pharmaceutical companies have continued research on delivering aminoglycosides via aerosol. Presently, two companies (Transave Inc and Bayer Healthcare with Nektar Therapeutics) are on the forefront of this research. Transave Inc (Monmouth Junction, NJ) reported positive results from a phase 2 trial of its investigational drug ArikaceTM (liposomal amikacin for inhalation) for the treatment of cystic fibrosis patients who have lung infections due to P. aeruginosa.18 Bayer Healthcare is further ahead in the research and potential FDA approval of aerosol amikacin. Phase 2 and 3 studies have demonstrated amikacin inhale (trade name to be determined) to be effective for the treatment for serious and life-threatening pneumonia for mechanically ventilated patients.19 Amikacin inhale will be combined with Nektar Therapeutics’ LPT™ (liquid pulmonary technology). LPT is a microprocessor-controlled vibrating-mesh nebulizer that aerosolizes liquid amikacin without the need for a heat-generated piezoelectric crystal or pressurized jet of gas. Amikacin inhale of doses of 400 mg twice daily achieved pulmonary concentrations more than 25 times the minimum inhibitory concentration for the respiratory pathogen.20,21 Treatment for 7 to 14 days was associated with a decrease in IV antibiotics for pneumonia.22 Two phase 3 randomized, placebo-controlled studies began in 2009 at approximately 130 investigational sites in the United States, Europe, and Asia.19 The delivery platform of the aerosol or Nektar’s LPT aerosol generator produces aerosol particles of 3 to 5 µm diameter with a average delivery efficiency of approximately 43% compared to 10% to 15% with traditional nebulizers.23 The LPT device can work in-line with the ventilator circuit, or it can be configured to work with a handheld adapter. If approved, amikacin inhale would be the first aerosolized antibiotic for the treatment of pneumonia.
Pulmonary drug delivery of future pharmacotherapeutic agents will continue to evolve due to advances in pharmaceutics, drug delivery biotechnology, and novel delivery systems. The aerosol delivery method offers another choice for patients whose medications are currently administered through oral, intravenous, or subcutaneous routes. Respiratory care practitioners are on the forefront to assist and potentially administer these future pharmacotherapeutic agents. Based on this expanded role, the respiratory care practitioner will continue to be challenged to expand their therapeutic drug knowledge to optimize pharmaceutical drug delivery.
Michael J. Cawley, PharmD, RPh, RRT, CPFT, is associate professor of clinical pharmacy, Philadelphia College of Pharmacy. For further information, contact [email protected]
- Global Pulmonary Drug Delivery Technologies Market Is Projected to Reach US$37.7 Billion by 2015, According to New Report by Global Industry Analysts. Available at: www.prweb.com/printer/3720994.htm. Accessed November 17, 2010.
- Lacy CF, Armstrong LL, Goldman MP, Lance LL, eds. Drug Information Handbook. 11th ed. Hudson, Ohio: Lexi-Comp Inc; 2008.
- Cayston® (aztreonam for inhalation solution): US prescribing information. Foster City, Calif: Gilead Sciences Inc; February 2010.
- Retsch-Bogart GZ, Quittner AL, Gibson RL, et al. Efficacy and safety of inhaled aztreonam lysine for airway pseudomonas in cystic fibrosis. Chest. 2009;135:1223-32.
- McCoy KS, Quittner AL, Oermann CM, et al. Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am J Respir Crit Care Med. 2008;178:921-8.
- Retsch-Bogart GZ, Burns JL, Otto KL, et al. A phase 2 study of aztreonam lysine for inhalation to treat patients with cystic fibrosis and Pseudomonas aeruginosa infection. Pediatr Pulmonol. 2008;43:47-58.
- Oermann CM, Retsch-Bogart GZ, Quittner AL, et al. An 18-month study of the safety and efficacy of repeated courses of inhaled aztreonam lysine in cystic fibrosis. Pediatr Pulmonol. Epub 2010 Jul 29.
- European Medicines Agency. Aztreonam lysine (Cayston®) powder and solvent for nebulizer solution: summary of product characteristics. Available at: www.ema.europa.eu/ema/index.jsp?curl=search.jsp~ Accessed July 16, 2010.
- PARI’s eFlow included in Gilead’s NDA submission for aztreonam lysine for inhalation. Available at: www.medicalnewstoday.com/articles/89823.php. Accessed July 16, 2010,
- Drugs.com. FDA Approves Dulera. Available at: www.drugs.com/newdrugs/~. Accessed November 17, 2010.
- Dulera® (mometasone furoate and formoterol fumarate dihydrate) Inhalation Aerosol: US prescribing information. Whitehouse Station, NJ: Schering Corp, a subsidiary of Merck & Co Inc; June 2010.
- Weinstein SF, Corren J, Murphy K, Nolte H, White M. Twelve-week efficacy and safety study of mometasone furoate/formoterol 200/10 microg and 400/10 microg combination treatments in patients with persistent asthma previously receiving high-dose inhaled corticosteroids. Allergy Asthma Proc. 2010;31:280-89.
- National Diabetes Information Clearinghouse. National Diabetes Statistics. Prevalence of Diagnosed and Undiagnosed Diabetes in the United States, All Ages, 2007. Available at: diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm#allages. Accessed November 12, 2010.
- Bloomberg Businessweek. New Inhaled Insulin Shows Promise for Diabetes. Available at: www.businessweek.com/lifestyle/content/healthday/637285.html. Accessed November 15, 2010.
- TapeBeat.com. Many Questions on Mannkind’s Afrezza. Available at: [removed]www.tapebeat.com/201004307357/Research/~[/removed]. Accessed November 9, 2010.
- FierceBiotech.com. MannKind’s inhaled insulin drug Afrezza delayed. Available at: www.fiercebiotech.com/story/mannkinds-inhaled-insulin-drug-afrezza-delayed/2010-03-15. Accessed November 9, 2010.
- TOBI® (tobramycin inhalation solution); US prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corp; November 2009.
- PARI Pharma. Transave announces positive phase ii results for once-daily Arikace™ in the treatment of cystic fibrosis patients who have pseudomonas lung infections. Available at: [removed]www.paripharma.com/news3c.htm[/removed]. Accessed November 11, 2010.
- Nektar Therapeutics. White Paper. Amikacin Inhale: the therapeutic potential of a new aerosol treatment for mechanically ventilated patients with Gram-negative pneumonia. Available at: www.nektar.com/pdf/pipeline/NKTR-061/AmikacinInhaleWhitePaper.pdf. Accessed November 18, 2010.
- Chastre J. NKTR-061 achieves safe serum concentrations after repeat dosing in intubated, mechanically ventilated patients with Gram-negative pneumonia: a pharmacokinetic study (poster 720). Presented at: 2007 ATS International Conference; May 18-23; San Francisco.
- Niederman MS. NKTR-061 (inhaled amikacin) achieves high tracheal aspirate concentrations in intubated, mechanically ventilated patients with Gram-negative pneumonia: a pharmacokinetic study (poster 719). Presented at: 2007 ATS International Conference; May 18-23; San Francisco.
- Niederman MS. NKTR-061 (inhaled amikacin) reduces intravenous antibiotic use in intubated mechanically ventilated patients during treatment of Gram-negative pneumonia (poster 718). Presented at: 2007 ATS International Conference; May 18-23; San Francisco.
- Corkery K, Gribben D, Fink J, Eldon M, Niederman M. Evidence of high amikacin lung deposition in mechanically ventilated patients (MVP) with pneumonia and healthy subjects (HS) dosed using NKTR-061. Poster 517. Presented at: 2008 American Thoracic Society International Conference; May 19; Toronto..