US20080214481A1 - Methods of Treatment of Endobronchial Infections - Google Patents

Methods of Treatment of Endobronchial Infections Download PDF

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US20080214481A1
US20080214481A1 US11/570,584 US57058405A US2008214481A1 US 20080214481 A1 US20080214481 A1 US 20080214481A1 US 57058405 A US57058405 A US 57058405A US 2008214481 A1 US2008214481 A1 US 2008214481A1
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treatment
subjects
tpi
tobramycin
study
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Peter Challoner
Carlos Rodriguez
Emil Samara
Thomas E. Tarara
John D. Lord
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Novartis AG
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Novartis Vaccines and Diagnostics Inc
Nektar Therapeutics
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to new and improved methods for treatment of susceptible endobronchial infections in patients with dry powder formulations of aminoglycoside antibiotics, such as tobramycin.
  • Cystic fibrosis is the most common life-shortening genetic disease in the United States and Northern Europe, affecting approximately 30,000 individuals in the United States (Cunningham, J. C. et al., “ An Introduction to Cystic Fibrosis for Patients and Families,” 5th ed., Bethesda: Cystic Fibrosis Foundation (2003)) and a similar number of individuals in Western Europe.
  • the genetic defect in this autosomal recessive disease is a mutation in the CF transmembrane conductance regulator (CFTR) gene, which codes for a chloride-channel protein (Collins, F.
  • Respiratory disease is a major cause of morbidity and accounts for 90% of mortality in persons with CF (Cystic Fibrosis Foundation, Cystic Fibrosis Foundation Patient Registry 2003 Annual Data Report , Bethesda, Md.: Cystic Fibrosis Foundation, (2004); Davis, P. B. et al., “Cystic fibrosis,” Amer J. Respir Crit Care Med 154(5):1229-56 (1996)).
  • Lung function (measured as forced expiratory volume at 1 second (FEV 1 % predicted) is a significant predictor of survival in CF.
  • CF patients suffer from thickened mucus caused by perturbed epithelial ion transport that impairs lung host defenses, resulting in increased susceptibility to early endobronchial infections with Staphylococcus aureus, Haemophilus influenzae , and P. aeruginosa .
  • Staphylococcus aureus aphylococcus aureus
  • Haemophilus influenzae a majority of persons with CF have P. aeruginosa present in their sputum ( Cystic Fibrosis Foundation Patient Registry 2003 Annual Data Report (2004)).
  • Chronic endobronchial infections, particularly with P. aeruginosa provoke a persistent inflammatory response in the airway that accelerates progressive obstructive disease characterized by diffuse bronchiectasis (Davis, P. B.
  • parenteral antipseudomonal antibiotics typically including an aminoglycoside.
  • parenteral aminoglycosides as highly polar agents, penetrate poorly into the endobronchial space.
  • serum levels approaching those associated with nephro-, vestibule-, and oto-toxicity are required (“American Academy of Otolaryngology. Guide for the evaluation of hearing handicap,” JAMA 241(19):2055-9 (1979); Brummett, R. E., “Drug-induced ototoxicity,” Drugs 19:412-28 (1980)).
  • TOBI® tobramycin solution for inhalation, a preservative-free, stable, and convenient formulation of tobramycin (60 mg/mL tobramycin in 5 mL of 1 ⁇ 4 normal saline) for administration via jet nebulizer, developed by PathoGenesis Corporation, Seattle, Wash. (now Chiron Corporation, Emeryville, Calif.).
  • TOBI® tobramycin solution for inhalation
  • tobramycin 60 mg/mL tobramycin in 5 mL of 1 ⁇ 4 normal saline
  • jet nebulizer developed by PathoGenesis Corporation, Seattle, Wash. (now Chiron Corporation, Emeryville, Calif.).
  • the combination of a 5 mL BID TOBI dose (300 mg tobramycin) and the PARI LC PLUS/PulmoAide compressor delivery system was approved by the FDA under NDA 50-753, December 1997, as a chronic intermittent therapy for the management of P.
  • aeruginosa in CF patients and remains the industry standard for this purpose.
  • the process of inhalation of the commercially available 300 mg TOBI dose can take 20 minutes per dose with additional time required for set-up and nebulizer cleaning.
  • the aerosol administration of a 5 ml dose of a formulation containing 300 mg of tobramycin in quarter normal saline for the suppression of P. aeruginosa in the endobronchial space of a patient is also disclosed in U.S. Pat. No. 5,508,269, the disclosure of which is incorporated herein in its entirety by this reference.
  • Tobramycin is an aminoglycoside antibiotic produced by the actinomycete, Streptomyces tenebrarius .
  • Low concentrations of tobramycin ( ⁇ 4 ⁇ g/mL) are effective in inhibiting the growth of many Gram-negative bacteria and under certain conditions may be bactericidal (Neu, H. C., “Tobramycin: an overview,” J Infect Dis 134: Suppl: S3-19 (1976)).
  • Tobramycin is poorly absorbed across mucosal surfaces, conventionally necessitating parenteral administration.
  • tobramycin activity is inhibited by purulent sputum: high concentrations of divalent cations, acidic conditions, increased ionic strength and macromolecules that bind the drug all inhibit tobramycin in this environment.
  • aeruginosa strains highly resistant to tobramycin (defined as MIC ⁇ 128 ⁇ g/mL) was comparable in the placebo and treatment groups.
  • the presence in the sputum of Gram-negative organisms other than P. aeruginosa intrinsically resistant to tobramycin occurred with equal frequency during administration of tobramycin or placebo (Ramsey, B. et al., “Response to Letter to the Editor: Aerosolized Tobramycin in Patients with Cystic Fibrosis,” N Engl J Med 329:1660 (1993)).
  • a randomized, crossover study compared the ability of several nebulizers to deliver tobramycin by measuring peak sputum tobramycin concentrations in samples collected ten minutes after completion of the aerosol dose.
  • This study administered TOBI® tobramycin solution for inhalation, PathoGenesis Corporation, Seattle, Wash. (now Chiron Corporation, Emeryville, Calif.), containing 60 mg/mL tobramycin in 5 mL one quarter (1 ⁇ 4) normal saline, using the PARI® LC jet nebulizer, PARI Respiratory Equipment, Inc., Richmond, Va.
  • This delivery system was shown to deliver a mean peak sputum tobramycin concentration of 678.8 ⁇ g/g (s.d.
  • the one-way valves in the PARI® LC PLUS have been described as permitting the delivery of more drug than the PARI® LC jet nebulizer, while decreasing the potential for accidental spillage and allowing for the use of an expiratory filter.
  • mean peak sputum tobramycin concentrations achieved using the PARI LC PLUS jet nebulizer are significantly higher than those using the PARI® LC jet nebulizer as described in Eisenberg et al. (1997), supra.
  • U.S. Pat. No. 6,890,907 and United States Published Patent Application 2003/0143162 A1 disclose that patients suffering from an endobronchial infection can be effectively treated by administering to the patient for inhalation a dose of 4.0 ml, or less, of a nebulized liquid aerosol formulation comprising from about 60 to about 200 mg/ml of an aminoglycoside antibiotic, such as tobramycin, in a physiologically acceptable carrier, in a time period of less than about 10 minutes.
  • the more efficient administration of the aminoglycoside formulation permits substantially smaller volumes of liquid aminoglycoside than the conventional administration regime to be administered in substantially shorter periods of time, thereby reducing the costs of administration and drug waste.
  • the formulations were shown to contain a minimal yet efficacious amount of aminoglycoside formulated in a relatively small volume of a physiologically acceptable solution, thereby reducing irritation of the lungs after inhalation of the aminoglycoside formulation.
  • the present invention provides methods for the treatment of endobronchial infections in a patient, comprising administering to the endobronchial system of the patient a dry powder aerosol composition comprising from 90 to 130 mg of an aminoglycoside antibiotic one to three times a day for a first treatment period of 20 to 36 days.
  • the first treatment period may be followed by a second non-treatment period wherein no aminoglycoside antibiotic is administered to the endobronchial system of the patient.
  • the cycle of the first treatment period of aminoglycoside treatment followed by the second non-treatment period wherein no aminoglycoside antibiotic is administered to the endobronchial system of the patient may be repeated two or more times until the desired antibacterial effect is obtained.
  • the first and second treatment periods may be repeated a multiplicity of times throughout the medical treatment of the patient.
  • the methods of the invention are useful for treating any endobronchial infection that is susceptible to an aminoglycoside antibiotic, such as a pseudomonal endobronchial infection associated with cystic fibrosis.
  • FIG. 1 shows mean serum concentration of tobramycin in subjects at various times after administration of a defined dosage of TPI and TOBI.
  • FIG. 2 shows a plot of dosage of Tobramycin Powder for Inhalation (TPI) and Tobramycin Solution for Inhalation (TOBI) versus Area Under the Curve (AUC) (0,12).
  • FIG. 3 shows a plot of dosage of TPI and TOBI versus AUC (0, ⁇ ).
  • FIG. 4 shows the average concentration of tobramycin in sputum of subjects who had received a defined dosage of TOBI or TPI.
  • the present invention provides methods for the treatment of endobronchial infections in a patient, comprising administering to the endobronchial system of the patient a dry powder aerosol composition comprising from 90 to 130 mg of an aminoglycoside antibiotic one to three times a day for a first treatment period of 20 to 36 days.
  • the first treatment period may be followed by a second non-treatment period wherein no aminoglycoside antibiotic is administered to the endobronchial system of the patient.
  • the cycle of the first treatment period of aminoglycoside treatment followed by the second non-treatment period wherein no aminoglycoside antibiotic is administered to the endobronchial system of the patient may be repeated two or more times until the desired antibacterial effect is obtained.
  • the first and second treatment periods may be repeated a multiplicity of times throughout the medical treatment of the patient.
  • the present invention provides the use of an aminoglycoside antibiotic in the preparation of a medicament for the treatment of endobronchial infections in a patient by administering to the endobronchial system of the patient in a first treatment period a dry powder aerosol composition comprising from 90 to 130 mg of an aminoglycoside antibiotic one to three times a day for a first treatment period of 20 to 36 days.
  • the first treatment period may similarly be followed by a second non-treatment period wherein no aminoglycoside antibiotic is administered to the endobronchial system of the patient, and the first and second treatment periods may be repeated, substantially as described herein.
  • the methods of this aspect of the invention each include the step of administering, by inhalation, to a human or animal subject, in need of such administration, a therapeutically effective amount of an aerosol powder comprising 20% by weight to 90% by weight of an aminoglycoside antibiotic and a physiologically acceptable carrier, wherein the powder comprises particles, and wherein at least 50% of the particles have an aerodynamic diameter in the range of from 1 ⁇ m to 5 ⁇ m.
  • endobronchial infection refers to a bacterial infection located within a bronchus of the lungs.
  • examples of endobronchial infections that can be treated using the methods of the present invention include infections by gram negative organisms, such as Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, Burkholderia cepacia, Stenotrophomonas maltophilia , and Alcaligenes xiloxidants .
  • the methods of this aspect of the present invention can be used, for example, to treat human beings suffering from an endobronchial infection associated with cystic fibrosis, such as, e.g., a Pseudomonas aeruginosa infection.
  • Aminoglycoside antibiotics useful in the practice of the invention include, for example, gentamicin, amikacin, kanamycin, streptomycin, neomycin, netilmicin, paramecin and tobramycin.
  • a presently preferred aminoglycoside antibiotic for use in the practice of the present invention is tobramycin.
  • the aminoglycoside antibiotic is typically administered in the form of a pharmaceutically acceptable salt (e.g., sulfate, citrate, ascorbate, gluconate, carbonate, tartarate, succinate, acetate, or phosphate) or ester.
  • the aerosol powder is inhaled by the human or animal subject, and thereby enters the lungs of the human or animal subject.
  • the aerosol powder comprises particles that comprise the aminoglycoside antibiotic. It has been found that aerosol powders (comprising an aminoglycoside antibiotic) wherein at least 50% of the particles have an aerodynamic diameter in the range of from 1 ⁇ m to 5 ⁇ m effectively penetrate into the lungs of the human or animal subject, thereby effectively delivering the aminoglycoside antibiotic to the lungs of the subject.
  • some aerosol powders (comprising an aminoglycoside antibiotic) useful in the practice of the present invention comprise particles wherein at least 60% of the particles, or at least 70% of the particles, or at least 80% of the particles, or at least 90% of the particles, or at least 95% of the particles, have an aerodynamic diameter in the range of from 1 ⁇ m to 5 ⁇ m.
  • aerodynamic diameter refers to the diameter of a unit-density sphere having the same terminal settling velocity as the particle in question (see, e.g., “Aerosol Measurement: Principles, Techniques and Applications”. Edited by Klaus Willeke and Paul A. Baron. Van Nostrand Reinhold, New York, 1993). Aerodynamic diameter is used, for example, to predict where such particles will be deposited in the respiratory tract.
  • Mass median aerodynamic diameter (abbreviated as MMAD) is a measure of the aerodynamic size of a dispersed particle.
  • the aerodynamic size distribution defines the manner in which an aerosol deposits during inhalation, and is the diameter of a unit density sphere having the same settling velocity, generally in air, as the particle.
  • the aerodynamic diameter encompasses particle shape, density and physical size of a particle.
  • the aerodynamic size distribution may be characterized by the mass median aerodynamic diameter (MMAD).
  • MMAD refers to the midpoint or median of the aerodynamic particle size distribution of an aerosolized powder determined by Anderson cascade impaction.
  • cascade impaction devices include a series of screens of decreasing pore size.
  • the screens trap particles within a moving jet that passes through the impactor.
  • the amount of particulate material (having particle sizes within a defined size range) that is trapped on each screen can be determined by washing the screen and measuring the amount of eluted material. Examples of cascade impactors, and their use, are described in Chapter 601 (Aerosols) of the Pharmacopoeia of the United States (26th Revision), the cited portion of which publication is incorporated herein by reference.
  • the powdered aminoglycoside antibiotic formulations useful in the practice of the present invention typically contain less than 15% by weight moisture, usually below about 11% by weight, and preferably below about 8% by weight.
  • a therapeutically effective amount of an aerosol powder comprising an aminoglycoside antibiotic is administered by inhalation to a patient suffering from an endobronchial infection.
  • a therapeutically effective amount of an aerosol powder contains sufficient aminoglycoside antibiotic to completely or partially inhibit the growth of susceptible bacteria in the lungs of the patient.
  • aminoglycoside tobramycin therapeutically effective amounts are obtained by administering to a patient from once daily to three times a day, and in preferred aspects of the invention twice a day, an aerosol powder compositions comprising a dosage from about 90 mg to about 130 mg, more preferably from about 100 mg to about 120 mg, and most preferably from about 110 mg to about 115 mg of tobramycin (determined as free-base weight excluding the weight of counterion(s) that may be present).
  • the dosage of administered aminoglycoside such as tobramycin
  • the administered dosage of aminoglycoside antibiotic may be divided into two to six unit doses, more preferably three to five unit doses and even more preferably four unit doses.
  • a dosage for administration of 112 mg of tobramycin (determined as free-base weight excluding the weight of counterion(s) that may be present) is loaded into 4 separate #2 HPMC capsules at fill weights of 27 mg of tobramycin as free base per capsule.
  • the dry powder aerosol compositions of the invention are administered to a patient for a first treatment period of from 20 to 36 days, more preferably from 26 to 30 days, and even more preferably for about 28 days.
  • This first treatment period is followed by a second non-treatment period wherein no aminoglycoside antibiotic is administered to the endobronchial system of the patient.
  • the second non-treatment period will continue for about 20 to 36 days, more preferably from about 26 to about 30 days, and most preferably for about 28 days.
  • the methods of the invention are used to treat cystic fibrosis patients for management of chronic Pseudomonas aeruginosa infections.
  • the invention contemplates the treatment of a cystic fibrosis patient suffering from an endobronchial infection, comprising administering to endobronchial system of the patient a dry powder aerosol composition comprising from 110 to 115 mg of tobramycin antibiotic twice a day for a first treatment period of 28 days, providing a second non-treatment period of from 26 to 30 days wherein no tobramycin antibiotic is administered to the endobronchial system of the patient, and then repeating the first and second treatment periods.
  • the 110 to 115 mg dosage of tobramycin may be divided into three to five unit doses, preferably into four unit doses, for sequential administration. Since cystic fibrosis patients tend to be chronically infected with P. aeruginosa , the cycle of treatment for the first treatment period followed by the second non-treatment period will typically be repeated a plurality or multiplicity of times, and may be continued indefinitely for long term management of endobronchial infections in the cystic fibrosis patient.
  • the aerosol powder typically comprises from 20% (by weight) to 90% (by weight) of aminoglycoside antibiotic.
  • the aerosol powder comprises from 30% (by weight) to 80% (by weight) of an aminoglycoside antibiotic.
  • the aerosol powder comprises from 40% (by weight) to 70% (by weight) of an aminoglycoside antibiotic.
  • the percentage (by weight) of the aminoglycoside antibiotic refers to the amount of the free antibiotic, excluding the weight of counterion(s) that may be present.
  • Aerosol powders of the invention typically, but not necessarily, include at least one physiologically acceptable carrier.
  • the aerosol powder can include one or more excipients, and/or any other component that improves the effectiveness of the aminoglycoside antibiotic.
  • excipients may serve simply as bulking agents when it is desired to reduce the active agent concentration in the powder which is being delivered to a patient.
  • excipients may also serve to improve the dispersability of the powder within a powder dispersion device in order to provide more efficient and reproducible delivery of the active agent and to improve the handling characteristics of the active agent (e.g., flowability and consistency) to facilitate manufacturing and powder filling.
  • the excipient materials can often function to improve the physical and chemical stability of the aminoglycoside, to minimize the residual moisture content and hinder moisture uptake, and to enhance particle size, degree of aggregation, surface properties (e.g., rugosity), ease of inhalation, and targeting of the resultant particles to the deep lung.
  • compositions useful in the practice of the present invention include, but are not limited to, proteins, peptides, amino acids, lipids, polymers, and carbohydrates (e.g., sugars, including monosaccharides, di-, tri-, tetra-, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars; and polysaccharides or sugar polymers), which may be present singly or in combination.
  • Exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, and casein.
  • Representative amino acid/polypeptide components which may also function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, proline, isoleucine, valine, methionine, phenylalanine, and aspartame, although arginine is less preferred.
  • Polyamino acids of the representative amino acids such as di-leucine and tri-leucine are also suitable for use with the present invention.
  • Carbohydrate excipients suitable for use in the invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, and sorbose; disaccharides, such as lactose, sucrose, trehalose, cellobiose; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, and starches; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), and myoinositol.
  • monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, and sorbose
  • disaccharides such as lactose, sucrose, trehalose, cellobiose
  • polysaccharides such as
  • the aminoglycoside compositions may also include a buffer or a pH adjusting agent; typically, the buffer is a salt prepared from an organic acid or base.
  • Representative buffers include organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris, tromethamine hydrochloride, or phosphate buffers.
  • aminoglycoside compositions useful in the practice of the invention may include polymeric excipients/additives such as polyvinylpyrrolidones, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, Ficolls (a polymeric sugar), dextran, dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl- ⁇ -cyclodextrin, hydroxyethyl starch), polyethylene glycols, pectin, salts (e.g., sodium chloride), antioxidants, antistatic agents, surfactants (e.g., polysorbates such as “TWEEN 20” and “TWEEN 80”, lecithin, oleic acid, benzalkonium chloride, and sorbitan esters), lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol), and chelating agents (e.g., EDTA).
  • lecithin is a member of the phosphatidylcholine group of naturally-occurring phospholipids that act as surfactants in mammalian (including human) lungs.
  • the aminoglycoside compositions useful in the practice of the invention may include a dispersing agent for improving the intrinsic dispersability properties of the aminoglycoside powders.
  • Suitable agents are disclosed in PCT applications WO 95/31479, WO 96/32096, and WO 96/32149, hereby incorporated in their entirety by reference.
  • suitable agents include water soluble polypeptides and hydrophobic amino acids such as tryptophan, leucine, phenylalanine, and glycine. Leucine and tri-leucine are particularly preferred for use according to this invention.
  • the solid state matrix formed by the aminoglycoside and excipient imparts a stabilizing environment to the aminoglycoside.
  • the stabilizing matrix may be crystalline, an amorphous glass, or a mixture of both forms. Most suitable are dry powder formulations which are a mixture of both forms.
  • dry powder formulations which are a mixture of both forms.
  • T g is at least 20° C. above the storage temperature.
  • the aminoglycoside compositions comprise a phospholipid as the solid state matrix as disclosed in WO 99/16419 and WO 01/85136, hereby incorporated in their entirety by reference.
  • Dry powder aminoglycoside compositions may be prepared by spray drying under conditions which result in a substantially amorphous glassy or a substantially crystalline bioactive powder as described above. Spray drying of the aminoglycoside-solution formulations is carried out, for example, as described generally in the “Spray Drying Handbook,” 5th ed., K. Masters, John Wiley & Sons, Inc., NY, N.Y. (1991), and in WO 97/41833, the contents of which are incorporated herein by reference.
  • an aminoglycoside is generally dissolved in a physiologically acceptable solvent such as water.
  • a physiologically acceptable solvent such as water.
  • the pH range of solutions to be spray-dried is generally maintained between about 3 and 10, preferably 5 to 8, with near neutral pHs being preferred, since such pHs may aid in maintaining the physiological compatibility of the powder after dissolution of powder within the lung.
  • the aqueous formulation may optionally contain additional water-miscible solvents, such as alcohols, acetone, and the like. Representative alcohols are lower alcohols such as methanol, ethanol, propanol, isopropanol, and the like.
  • Aminoglycoside solutions will generally contain aminoglycoside dissolved at a concentration from 0.05% (weight/volume) to about 20% (weight/volume), usually from 0.4% to 5.0% (weight/volume).
  • the aminoglycoside-containing solutions are then spray dried in a conventional spray drier, such as those available from commercial suppliers such as Niro A/S (Denmark), Buchi (Switzerland), and the like, resulting in a stable, aminoglycoside dry powder.
  • Optimal conditions for spray drying the aminoglycoside solutions will vary depending upon the formulation components, and are generally determined experimentally.
  • the gas used to spray dry the material is typically air, although inert gases such as nitrogen or argon are also suitable.
  • the temperature of both the inlet and outlet of the gas used to dry the sprayed material is such that it does not cause deactivation of aminoglycoside in the sprayed material. Such temperatures are typically determined experimentally, although generally, the inlet temperature will range from about 50° C. to about 200° C. while the outlet temperature will range from about 30° C. to about 150° C.
  • Aminoglycoside dry powders may also be prepared by lyophilization, vacuum drying, spray freeze drying, super critical fluid processing, or other forms of evaporative drying or by blending, grinding, or jet milling formulation components in dry powder form.
  • the aminoglycoside powders may be prepared by agglomerating the powder components, sieving the materials to obtain the agglomerates, spheronizing to provide a more spherical agglomerate, and sizing to obtain a uniformly-sized product, as described, e.g., in WO 95/09616, incorporated herein by reference.
  • the aminoglycoside dry powders are preferably maintained under dry (i.e., relatively low humidity) conditions during manufacture, processing, and storage.
  • an exemplary powdered tobramycin formulation useful in the practice of the present invention may be made according to the emulsification/spray drying process disclosed in WO 99/16419 and WO 01/85136 cited above.
  • Formulations according to such embodiments are engineered to comprise dry powder particles comprising at least 75% w/w tobramycin, preferably at least 85% w/w tobramycin, 2-25% w/w of a phospholipid, preferably 8-18% w/w, and 0-5% w/w of a metal ion such as calcium chloride.
  • the particles of this embodiment generally have an MMAD of from 1 micron to 5 microns, and a bulk density of greater than 0.08 g/cm 3 , preferably greater than 0.12 g/cm 3 .
  • Another exemplary powdered tobramycin formulation useful in the practice of the present invention may be produced by creating an emulsion containing active tobramycin, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), CaCl 2 and perfluorooctyl bromide (PFOB).
  • This feedstock emulsion is then sprayed through an atomizer nozzle, producing fine droplets.
  • water and PFOB evaporate yielding phospholipid-based spherical particles with porous structure.
  • These spheres are of low density and thus demonstrate favorable aerodynamic characteristics (e.g., the spherical particles have an aerodynamic diameter in the range of from 1 ⁇ m to 5 ⁇ m). Their high surface porosity also reduces particle-to-particle contact, decreasing the energy required for aerosol suspension.
  • the aerosol powder (comprising an aminoglycoside antibiotic) can be administered using a dry powder inhaler that uses a patient's (e.g., human's or animal's) inhaled breath to deliver the powdered aminoglycoside antibiotic formulation to the lungs.
  • a dry powder inhaler is the model T-326 inhaler (Nektar Therapeutics, 150 Industrial Road, San Carlos, CA 94070, U.S.A.).
  • Other examples of useful dry powder inhalation devices are described in U.S. Pat. Nos. 5,458,135; 5,740,794; 5,775,320; and 5,785,049, each of which patents are incorporated herein by reference.
  • the powdered medicament When administered using a device of this type, the powdered medicament is contained in a receptacle having a puncturable lid or other access surface, preferably a blister package or cartridge, where the receptacle may contain a single dosage unit or multiple dosage units. Exemplary methods for filling large numbers of cavities with metered doses of dry powder medicament are described in U.S. Pat. No. 5,826,633, incorporated herein by reference.
  • dry powder inhalers of the type described, for example, in U.S. Pat. Nos. 3,906,950, 4,013,075, 4,069,819, and 4,995,385, each of which patents are incorporated herein by reference, wherein a premeasured dose of aminoglycoside dry powder for delivery to a subject is contained within a capsule, such as a hard gelatin capsule.
  • a capsule such as a hard gelatin capsule.
  • the size of the capsule such as 00, 0, No. 1, or No. 3 sized capsules, depends, among other factors, upon the inhalation device used to administer the powders.
  • dry powder dispersion devices for pulmonarily administering aminoglycoside dry powders include those described, for example, in EP 129985, EP 472598, EP 467172, and U.S. Pat. No. 5,522,385, each of which patents are incorporated herein in their entirety by reference.
  • inhalation devices such as the Astra-Draco “TURBUHALER”. This type of device is described in detail in U.S. Pat. Nos. 4,668,218, 4,667,668, and 4,805,811, all of which are incorporated herein by reference.
  • a therapeutically effective amount of an aerosol powder (comprising an aminoglycoside antibiotic) can be administered from a single container, or from more than one container, disposed within a dry powder inhalation device.
  • a dry powder inhalation device may be loaded with a single container containing a therapeutically effective amount of an aerosol powder (comprising an aminoglycoside antibiotic), and the contents of the container are inhaled by a human or animal subject.
  • a dry powder inhaler may be loaded with multiple unit dose containers (e.g., 2, 3, or 4 containers), such as #2 HPMC capsules, that separately contain less than a therapeutically effective amount of an aerosol powder (comprising an aminoglycoside antibiotic), but which together contain a therapeutically effective amount of the aerosol powder.
  • the dry powder inhaler discharges the contents of all of the containers disposed therein, and thereby provides the user with a therapeutically effective amount of the aerosol powder.
  • the aminoglycoside treatment regimen of the present invention may be used alone or in combination with one or more additional agents for the treatment of endobronchial infections, particularly infections by P. aeruginosa .
  • the one or more additional agents for the treatment of endobronchial infections may be administered during the first treatment period of aminoglycoside treatment, during the second non-treatment period wherein no aminoglycoside antibiotic is administered to the endobronchial system of the patient, or during both the first and second treatment periods.
  • the one or more additional agents for the treatment of endobronchial infections is administered during the second non-treatment period wherein no aminoglycoside antibiotic is administered to the endobronchial system of the patient.
  • Suitable additional agents for the treatment of endobronchial infections include, for example, non-aminoglycoside antiinfective agents, such as monobactam, ⁇ -lactam, macrolide, fluoroquinolone and/or glycopeptide antibiotic compounds.
  • non-aminoglycoside antiinfective agent may be aztreonam.
  • the emitted dose (ED) of the powdered aminoglycoside antibiotic formulations will generally be greater than 50%. More preferably, the ED of the powdered aminoglycoside antibiotic formulations useful in the practice of the present invention is greater than 70%, and is often greater than 80%.
  • the term “emitted dose” or “ED” refers to an indication of the delivery of dry powder from a suitable inhaler device after a firing or dispersion event from a powder unit, capsule, or reservoir. ED is defined as the ratio of the dose delivered by an inhaler device to the nominal dose (i.e., the mass of powder per unit dose placed into a suitable inhaler device prior to firing).
  • the ED is an experimentally-determined amount, and is typically determined using an in-vitro device set up which mimics patient dosing.
  • a nominal dose of dry powder (as defined above) is placed into a suitable dry powder inhaler, which is then actuated, dispersing the powder.
  • the resulting aerosol cloud is then drawn by vacuum from the device, where it is captured on a tared filter attached to the device mouthpiece. The amount of powder that reaches the filter constitutes the delivered dose.
  • kits for use in the treatment of endobronchial infections in a patient comprising one or more doses of from 90 to 130 mg of a dry powder aminoglycoside antibiotic together with instructions for administration of a dosage to the endobronchial system of the patient using a dry powder inhalation device one to three times a day for a first treatment period of 20 to 36 days.
  • the instructions may further provide that the first treatment period may be followed by a second non-treatment period wherein no aminoglycoside antibiotic is administered to the endobronchial system of the patient, and that the cycle of the first treatment period of aminoglycoside treatment followed by the second non-treatment period wherein no aminoglycoside antibiotic is administered to the endobronchial system of the patient may be repeated two or more times until the desired antibacterial effect is obtained, substantially as described herein.
  • the one or more doses may be contained in a single container as a single unit dose, or it may be divided into multiple containers or units doses for sequential administration, depending of the inhalation device used for delivery of the antibiotic.
  • the administered dosage of aminoglycoside antibiotic may be divided into two to six unit doses, more preferably three to five unit doses and even more preferably four unit doses.
  • the kits of the invention contain dosages for administration of 112 mg of tobramycin (determined as free-base weight excluding the weight of counterion(s) that may be present) loaded into 4 separate #2 HPMC capsules at fill weights of 27 mg of tobramycin as free base per capsule.
  • a tobramycin sulfate dry powder composition is prepared according to the following procedure.
  • SWFI Sterile Water for Irrigation
  • DSPC disteroyl phosphatidylcholine
  • DSPC and calcium chloride dihydrate are then added to the heated water.
  • the resulting lipid dispersion is mixed in an UltraTurrax T-50 (IKA Labortechnik) at 8,000 rpm for 5 min.
  • Perfluorooctyl bromide (PFOB) is then added dropwise (15 ml/min) to the lipid dispersion under mixing. After the addition is complete the resulting PFOB-in-water emulsion is mixed for an additional 10 min at 10,000 rpm.
  • Emulsification in the UltraTurrax produces droplets in the micron-size range.
  • Tobramycin sulfate is then dissolved in the continuous phase of the emulsion and the resulting dispersion is used as the feedstock for spray drying.
  • the feedstock is then spray dried to obtain a dry powder formulation having the composition set forth in Table 1 below.
  • the powder is placed into a capsule filling station at a relative humidity of 10 to 15% and allowed to equilibrate for 10 minutes, and then filled into #2 HPMC capsules at a fill weight of 50 mg (27 mg of tobramycin as free base) per capsule.
  • This Example describes a clinical study that demonstrates that single dose administration of a tobramycin dry powder composition of the invention results in a more efficient delivery of tobramycin than administration of a tobramycin solution, while maintaining similar tobramycin pharmacokinetics.
  • the study was designed as a randomized, open-label, sequential-cohort, active-controlled, single-dose, dose-escalation study.
  • subjects were randomized in a 3:1 ratio to receive either a single dose of Tobramycin Powder for Inhalation (TPI) administered using a T-326 Inhaler (Nektar Therapeutics, San Carlos, CA, USA), according to the dosing schedule shown below, or a single dose of 300 mg Tobramycin Solution for Inhalation (TOBI), aerosolized by a PARI LC PLUSTM jet nebulizer with a DeVilbiss PulmoAideTM compressor. Subjects were allowed to participate in one cohort only.
  • TPI Tobramycin Powder for Inhalation
  • TOBI Tobramycin Solution for Inhalation
  • Escalation to the next TPI treatment cohort proceeded after review by a Data Monitoring Committee (DMC) of all treatment-emergent adverse events (AEs) and other safety results of the completed cohort and if neither of the following criteria were met: Three or more subjects within a cohort treated with TPI experience at least a 20% relative decline in FEV 1 within 30 minutes after the end of dosing; any TPI-dosed subject experienced a study drug-related Serious Adverse Event (SAE).
  • DMC Data Monitoring Committee
  • SAE Serious Adverse Event
  • TPI T-326 Inhaler
  • CF cystic fibrosis
  • Subjects were screened for eligibility 7 to 9 days prior to study drug administration. Subjects were evaluated for safety and for sputum and serum tobramycin concentrations at predose, at 30 minutes, and at 1, 2, 4, 8, and 12 hours after the single dose of study drug was administered under supervision. A 7-day ( ⁇ 2 days) follow-up visit was conducted.
  • the primary outcome measure for this study was the general safety and tolerability of the experimental treatment. To better assess this outcome, a 3:1 randomization scheme was chosen to maximize enrollment into the experimental treatment arm.
  • TOBI is indicated for the management of cystic fibrosis patients with P. aeruginosa.
  • Subjects or their parents or legal guardians could withdraw their consent to participate in the study at any time without prejudice.
  • the investigator could withdraw a subject if, in his or her clinical judgment, it was in the best interest of the subject or if the subject could not comply with the protocol. Whenever possible, the tests and evaluations listed for the termination visit were carried out.
  • Cohort 1 Two capsules of TPI (14 mg dosage strength)
  • TPI used in this study is a dry powder formulation of tobramycin and two excipients: 1,2 distearoyl-sn-glycero-3-phosphocholine (DSPC) and calcium chloride (CaCl 2 ). TPI was filled into individual size 2-hydroxypropylmethylcellulose (HPMC) capsules containing either 25 mg or 50 mg of powder. Two dosage strengths of tobramycin powder were used in the present study: 14 mg tobramycin per capsule and 28 mg tobramycin per capsule.
  • TOBI® Tobramycin Solution for Inhalation (300 mg/5 mL) is a sterile, non-pyrogenic, preservative-free antibiotic prepared for aerosolization.
  • Each mL of study drug contains 60 mg tobramycin and 2.25 mg sodium chloride in sterile water for injection, pH 6.0 ⁇ 0.5.
  • TOBI® Tobramycin Solution for Inhalation Subjects randomized to the control treatment received 300 mg of TOBI® Tobramycin Solution for Inhalation at 60 mg/mL.
  • TOBI® Tobramycin Solution for Inhalation was administered to subjects via a PARI LC PLUS jet nebulizer and DeVilbiss PulmoAide Compressor.
  • the 300 mg dose of TOBI® Tobramycin Solution for Inhalation was supplied as a commercial ampoule of TOBI® Tobramycin Solution for Inhalation.
  • Two 5 mL ampoules of study drug were provided in a foil pouch. Although this was a single-dose study, a foil pouch containing two 5-mL ampoules of study drug was provided to subjects in the event that there was accidental spillage of the study medication during preparation and set-up of the nebulizer and delivery system.
  • TPI TPI
  • TPI was administered to subjects via a T-326 Inhaler.
  • TPI capsules were sealed in a double foil-wrapped, moisture-proof container and were to be administered within 30 minutes of opening the container.
  • T-326 Inhaler device only one T-326 Inhaler device was to be used to complete the single dose administration.
  • the T-326 Inhaler device was to be replaced after the second capsule was administered; therefore, two T-326 Inhalers were to be used to complete the single dose administration for these cohorts.
  • Eligible subjects were randomly assigned in a 3:1 ratio to either the experimental or control treatment group. Once the investigator or research coordinator confirmed that the subject met eligibility criteria, staff completed a randomization worksheet for the subject and received a subject number and treatment assignment via an Interactive Voice Response System (IVRS).
  • IVRS Interactive Voice Response System
  • the dose for the control treatment was the FDA-approved dose of 300 mg TOBI for the management of P. aeruginosa in CF patients 6 years of age and older.
  • the systemic bioavailability of the 300 mg dose of TOBI delivered via the PARI LC PLUS jet nebulizer/DeVilbiss PulmoAide compressor was estimated to be 11.7% of the nebulized dose.
  • the dose for the experimental treatment was two or four TPI capsules containing 14 mg tobramycin/capsule; or two, three, or four TPI capsules containing 28 mg tobramycin/capsule.
  • Subjects were given a single dose of either 300 mg TOBI® Tobramycin Solution for Inhalation at 60 mg/mL or a single dose of TPI consisting of two or four capsules of 14 mg dosage strength, or two, three, or four capsules of 28 mg dosage strength. There was no restriction on the timing of dosing in relation to meals.
  • Bronchodilators were administered only to subjects who routinely used bronchodilators for clinical therapy. Routine use is defined as once or more daily for two weeks prior to screening. Subjects on short-acting bronchodilators were administered the medication 15 to 60 minutes prior to the initiation of the study drug. Subjects on long-acting bronchodilators took the medication as prescribed in the preceding 24 hours.
  • the subject self-administered the single dose of study drug in the presence of the investigator or research coordinator.
  • Reasons for any premature termination, interruption, or delay in study drug administration were recorded on the source documentation and CRF.
  • Total study drug administration time was recorded on the source documentation and CRF.
  • Each subject (or parent/legal guardian if appropriate) in the care of the investigator provided written informed consent, including HIPAA authorization, and the subject assented (if appropriate) to participate in the study, before any study-related procedures were performed.
  • Investigators screened subjects at visit 1, seven to nine days before day 1 (visit 2) study drug administration, to determine eligibility for enrollment.
  • Investigators reviewed and recorded subjects' relevant medical history, including history of current disease and other pertinent respiratory history, baseline signs and symptoms, inhaled dry powder use and inhaled antibiotic use within 6 months before screening, and current medications and therapies ongoing at screening.
  • FEV 1 forced expiratory volume in 1 second
  • FVC forced vital capacity
  • F 25-75 mid-range forced expiratory flow rate
  • Subjects provided a blood sample for screening chemistry and hematology tests and a urine sample for dipstick proteinuria evaluation.
  • Female subjects who were 11 years or older or who had reached menarche provided a urine sample for pregnancy testing.
  • Subjects who satisfied all inclusion and exclusion requirements were eligible to participate in the study and were randomized to treatments as described in the protocol. Randomized subjects were to return to the clinic 7 to 9 days later (visit 2) to receive study treatment and treatment-related procedures.
  • TPI subjects currently using a short-acting bronchodilator either regularly or on demand could be pretreated with their short-acting bronchodilator at the discretion of the investigator.
  • Subjects not currently using a short-acting bronchodilator could be pretreated with one if they had a 10% or greater relative decline in FEV 1 between the screening and pre-dose pulmonary function tests. Relative percent change from screening in FEV 1 was calculated as follows.
  • Relative % FEV 1 change from screening [(predose FEV 1 ⁇ screening FEV 1 )/screening FEV 1 ] ⁇ 100
  • a single dose of study treatments was administered within 60 minutes after predose bronchodilator administration, if applicable, or spirometry, and subjects were evaluated for aerosol delivery and safety objectives of the protocol as described in following sections.
  • subjects were instructed to sit upright, breathe normally, and use nose clips during inhalation of study treatment.
  • the research coordinator recorded start and stop times for study treatment administration. If the subject experienced prolonged cough (greater than 10 seconds), the research coordinator stopped the timer and restarted it when the subject resumed treatment.
  • the Investigator and/or research coordinator noted whether a rattling sound emanating from the inhaler was heard on the second inhalation of the study drug.
  • subjects rinsed their mouths with 30 mL of normal saline, gargled for 5 to 10 seconds, and expectorated the rinse; this rinse procedure was performed three times.
  • Subjects remained at the clinic to complete safety assessments for 12 hours after the start of administration of study treatments. Subjects were then discharged from the clinic and scheduled to return to the clinic for visit 3 follow-up on day 8 ( ⁇ 2 days). Flexible scheduling of follow-up visits due to subject constraints (the follow-up visit is designated as “day 8” throughout this Example was permitted). Slight deviations from the protocol schedule were considered to have minimal or no effect on the evaluation of study objectives.
  • AEs study drug-related adverse events
  • Aerosol delivery characteristics of test and control treatments were determined on the basis of serum and sputum tobramycin concentrations over time, calculation of certain serum and sputum pharmacokinetic parameters as described in this Example, measurement of treatment administration time, and evaluation of T-326 Inhaler device and capsule performance.
  • Blood samples were collected at predose and at 0.5, 1, 2, 4, 8, and 12 hours after the start of the first tidal breath during inhalation of study treatment. Samples were to be collected as close as possible to specified times and were considered to have been drawn on time if collected within ⁇ 2 minutes of the scheduled 0.5-hour posttreatment collection time and within ⁇ 10 minutes of scheduled times for the ensuing posttreatment collections. Samples collected outside these intervals were considered protocol deviations.
  • Serum was harvested and stored at ⁇ 20° C. or below until analysis. Concentrations of tobramycin in serum were analyzed with a modified fluorescence polarization immunoassay (FPIA) method using the Abbott TDx®/TDxFLx® System. Samples were added directly to the dilution well of the sample cartridge. The net polarization was acquired by the TDx/TDxFLx apparatus. A weighted four-parameter logistic equation was used to calculate the concentrations of tobramycin. The concentrations of tobramycin were reported in terms of free base equivalents.
  • FPIA fluorescence polarization immunoassay
  • calibration standards 0.05, 0.10, 0.40, 0.80, and 0.90 ⁇ g/mL
  • quality control samples 0.05, 0.10, 0.40, and 0.80 ⁇ g/mL
  • the lower limit of quantitation was 0.05 ⁇ g/mL.
  • Sputum samples were expectorated by subjects from a deep cough and collected before day 1 dosing (predose) and at 0.5, 1, 2, 4, 8, and 12 hours after the start of the first tidal breath during inhalation of study treatment. Sputum samples were collected as close as possible to specified times and within the same time windows as the serum collections. Samples collected outside these intervals were considered protocol deviations.
  • a sputum sample (minimum of 100 mg) was collected before the single dose of study treatment to determine the baseline tobramycin concentration.
  • Subject sputum samples were first liquefied with 1 ⁇ 5 normal sodium hydroxide and diluted with Tris buffer (20.0 g Trizma base/L).
  • Sputum standard samples were prepared by spiking diluted pooled sputum from CF subjects with tobramycin to final concentrations of 0, 20, 40, 100, 200, 400, and 1000 ⁇ g/g of sputum.
  • Assay quality control samples were prepared by spiking diluted pooled sputum to contain 40, 300, and 800 ⁇ g/g.
  • the internal standard sisomycin (100 ⁇ L, 0.15 mg/mL in Tris buffer) was added to 100 ⁇ L of each standard, control, and subject sample, followed by 400 ⁇ L of acetonitrile and 50 ⁇ L of 2,4-dinitrofluorobenzene (0.17 g/mL).
  • the sample reaction mixtures were heated in a dry-block heater for 1 h at 80° C. After addition of 600 ⁇ L of 60/40 acetonitrile/water (v/v), 50 ⁇ L was analyzed by HPLC.
  • Retention time ranges of 3.8 to 4.1 min and 10.0 to 10.6 min were observed for tobramycin and sisomycin, respectively.
  • the lower limit of quantitation was 20 ⁇ g/g.
  • the concentrations of the standard samples were within 97 to 102% of the nominal concentration, with coefficients of variation (CV) not higher than 5.2%.
  • the accuracy of the method reflected by the interassay recoveries of the quality control samples, was 107%, 99%, and 97% for the 40, 300, and 800 ⁇ g/g quality control samples, respectively. Overall, this method exhibited suitable accuracy and precision for pharmacokinetic analysis.
  • Treatment administration time was defined as the length of time from the start of the subject's first inhalation to completion of treatment administration. Treatment administration was complete when the test T-326 Inhaler began to rattle and when the control PARI LC PLUS nebulizer began to sputter. The investigator noted, for TPI capsules, whether rattling was heard on the second breath by the subject, an indication that the capsule had been emptied.
  • An adverse event is defined as any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, at any dose, that does not necessarily have to have a causal relationship with this treatment.
  • An AE could therefore be any unfavorable and unintended sign (including abnormal laboratory findings), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
  • This definition includes intercurrent illnesses or injuries, and exacerbation of pre-existing conditions.
  • An unexpected AE is an event the nature or severity of which is not consistent with the applicable product information.
  • AEs may have been volunteered spontaneously by the subject or discovered as a result of general questioning by the investigator or research coordinator.
  • WBC white blood cell count
  • RBC red blood cell count
  • hemoglobin hemoglobin
  • differential differential
  • platelet count hematocrit
  • GTT gamma glutamyl transferase
  • ALT or SGPT alanine transaminase
  • AST or SGOT aspartate transaminase
  • alkaline phosphatase lactic dehydrogenase
  • LH lactic dehydrogenase
  • total bilirubin direct bilirubin
  • indirect bilirubin total protein
  • albumin album
  • the study protocol prospectively defined bronchospasm as a relative decline of 20% or more in FEV 1 % predicted from predose to 30 minutes after the end of dosing. Subjects with a relative decline of 10% or more in FEV 1 % predicted were also noted.
  • Vital signs were measured before the day 1 dose and at 30 minutes and 1, 4, 8, and 12 hours after the start of dosing and included sitting arterial blood pressure, heart rate, and respiratory rate taken after 10 minutes rest, and body temperature. Vital signs were also measured at the day 8 follow-up visit.
  • the measures of efficacy used in this study are standard, i.e., widely used and generally recognized as reliable, accurate, relevant, and discriminatory between effective and ineffective agents.
  • the measures of safety used in this study are standard clinical and laboratory procedures.
  • the concentration (C) versus time (t) data from sputum and serum tobramycin assays were analyzed by model-independent methods to obtain the pharmacokinetic parameters.
  • the maximum concentration (C max ) and the time to maximum concentration (t max ) were obtained by inspection.
  • the AUC to infinity, AUC(0, ⁇ ) was calculated as AUC(0,12)+C(12)/ ⁇ z where C(12) is the concentration 12 h after the start of dosing.
  • SD( ⁇ z ) is the standard error of the mean terminal rate constant at each dose.
  • a linear regression model was fitted for log AUC(0,12) vs. log (TPI dose) of TPI serum concentration data from all cohorts to estimate the comparable dose of TPI to TOBI.
  • the comparable dose and the 95% confidence interval were determined by taking the inverse of the fitted regression line and the upper and lower 95% confidence bands at the mean log AUC(0,12) of TOBI data.
  • GCP Good Clinical Practice
  • Data quality control was performed using Procedural Language/Sequential Query Language (PL/SQL) and SAS® software version 8.2 or higher (SAS Institute, Cary, N.C.). Analysis was performed using SAS software version 8.2 or higher, based on a predefined analysis plan. The estimated overall database error rate was 0.022% with an upper 95% confidence limit of 0.157% (rounded). This upper confidence limit is below the chosen standard of 0.5%.
  • P/SQL Procedural Language/Sequential Query Language
  • SAS® software version 8.2 or higher SAS Institute, Cary, N.C.
  • Serum AUC(0,12) was used to estimate the comparable TPI dose to TOBI.
  • a linear regression analysis with log AUC(0,12) as the dependent variable and log (TPI dose) as the independent variable was performed using the data from all TPI groups.
  • the comparable dose of TPI was determined by taking the inverse of the fitted regression line at the mean log AUC(0,12) of TOBI serum tobramycin concentrations from the five combined TOBI cohorts.
  • the study protocol identified no secondary aerosol delivery variables.
  • AE treatment-emergent adverse events
  • Normal values have been developed for FEV 1 , FVC 1 and FEF 25-75 (spirometry measurements) if subjects are free of pulmonary disease. These norms are commonly used in studies of subjects with pulmonary disease. Raw spirometry measurements were converted to normative percent predicted values using Knudson Equations, as described below. For each subject, the Knudson normative value for FEV 1 , FVC 1 or FEF 25-75 is a linear combination of the subject age (years) and height (cm) using the following formula:
  • coefficients C 0 , C 1 , and C 2 are determined based on subject gender and age group.
  • the percent (%) predicted value is calculated by:
  • Relative change [(Postdose FEV 1 % ⁇ Predose FEV 1 %) ⁇ Predose FEV 1 %] ⁇ 100
  • a subject was defined as experiencing bronchospasm when the relative change from baseline was a decline of ⁇ 20%.
  • Eighty-six of the 90 enrolled subjects were randomized, were administered a single dose of study treatment, and were evaluable for safety objectives of the protocol. Three of the 90 subjects were withdrawn from the study due to AEs before they received study treatment and were excluded from safety evaluations. One additional subject did not receive any study treatment due to the failure of the T-326 Inhaler to pierce the treatment capsules and was excluded from safety evaluations.
  • TPI and TOBI subjects were comparable in height and weight at screening.
  • bronchodilator Thirty-six of the 90 enrolled (i.e., both TPI and TOBI subjects) subjects used a short-acting bronchodilator as a part of their standard CF treatment within 15 to 60 minutes before study treatment. In two instances, bronchodilator use was more than 60 minutes before administration of study treatment.
  • mean serum concentration-time profiles of tobramycin after administration of TPI and TOBI indicate that the drug is rapidly absorbed: median t max was 1 h in all treatments. The distribution of the drug appears to be very fast, and the levels declined in a monoexponential fashion, with average terminal half-lives ranging between 2.8 and 3.5 h. The values of the pharmacokinetic parameters of tobramycin after TOBI administration are consistent with previous studies.
  • TPI administration time averaged nearly 16 minutes in TOBI subjects (Table 9).
  • administration time for two capsules of TPI averaged 1.7 and 2.5 minutes for the 2 ⁇ 14 mg and 2 ⁇ 28 mg doses, respectively.
  • Administration times averaged 4.2, 4.5, and 4.9 minutes for TPI 4 ⁇ 14 mg, 3 ⁇ 28 mg, and 4 ⁇ 28 mg doses, but in these cohorts a second device was unpacked and utilized for dosing of the third and fourth capsules, respectively.
  • TPI administration time increased primarily as the number of capsules increased and, secondarily, as the dosage strength increased.
  • TPI capsules All but two TPI capsules were administered as required (exception: 3 rd and 4 th capsules for one subject in the TPI 4 ⁇ 28 mg group). Rattling was heard on the second breath in 85% or more of the capsules.
  • the study was not designed or powered to show clinical or pharmacokinetic equivalence between the test product and the control.
  • TPI administration time averaged nearly 16 minutes in TOBI subjects.
  • administration time for two capsules of TPI averaged 1.7 and 2.5 minutes for the 2 ⁇ 14 mg and 2 ⁇ 28 mg doses, respectively; administration times averaged 4.2, 4.5, and 4.9 minutes for TPI 4 ⁇ 14 mg, 3 ⁇ 28 mg, and 4 ⁇ 28 mg doses.
  • TPI administration time increased primarily as the number of capsules increased and, secondarily, as the dosage strength increased.
  • TPI subjects 40 of 66 subjects, 60.6% than TOBI subjects (6 of 20, 30.0%) experienced treatment-emergent AEs during or after administration of single-dose study treatments.
  • TPI 4 ⁇ 28 mg subject experienced moderate cough and sputum increased on day 2 which persisted and led to hospitalization on the eighth day after the single-dose study treatment was administered. Therefore, on day 8 after the subject completed the study, these AEs were determined to be SAEs. Neither of these SAEs, which occurred in the same subject, was considered related to TPI treatment.
  • Another TPI 4 ⁇ 28 mg subject experienced the non-serious AEs of moderate, probably-related cough aggravated, dysgeusia, and lacrimation increased that caused study drug administration to be interrupted and then stopped; the subject then withdrew consent and was withdrawn from the study.
  • the incidence of cough, cough aggravated, and dysgeusia increased slightly with increasing TPI dose, but no conclusive trend in the incidence of any individual AE was observed in the data.
  • no more than one TOBI subject experienced any AE TOBI subjects experienced no cough, cough aggravated, or dysgeusia. However, most subjects dosed with TOBI (17 of 20, 85%) received TOBI as part of their usual therapy.
  • TPI subjects Forty of 66 TPI subjects and six of 20 TOBI subjects experienced treatment-emergent AEs during or after treatment. The percent of subjects with any AE was similar among the TPI dose levels. All treatment-emergent AEs were mild or moderate in intensity.
  • AEs experienced by the largest number of TPI subjects were cough or cough aggravated (13 of 66 subjects 19.7%); dysgeusia (11 subjects, 16.7%); pharyngitis, haemoptysis, and rhinorrhea (4 subjects, 6.1% each); sputum increased, crackles lung, lacrimation increased, abdominal pain upper, dizziness, headache NOS, and throat irritation (3 subjects, 4.5% each).
  • TOBI subjects experienced no cough, cough aggravated, or dysgeusia.
  • TPI 4 ⁇ 28 mg subject experienced SAEs on day 2 (moderate cough and sputum increased) that led to hospitalization for exacerbation of CF lung disease on the eighth day after the single-dose study treatment. Neither of these SAEs, which occurred in the same subject, was considered related to TPI treatment.
  • TPI 4 ⁇ 28 mg subject experienced moderate cough aggravated, dysgeusia, and lacrimation increased that caused study drug administration to be interrupted and then stopped, and the subject was withdrawn from the study. Each AE was considered to be probably related to TPI treatment by the investigator.
  • TOBI subject 12/405 had a clinically significant follow-up eosinophil result of 9.0% (normal range, 0 to 6%) that was recorded as an AE and was considered possibly related to TOBI treatment by the investigator.
  • the subject's baseline eosinophil result was at the upper limit of normal (5.9%), but the subject had elevated eosinophils 8 days before the baseline result.
  • the clinical importance of the final eosinophil result of 9.0% is uncertain.
  • TOBI subject and six other TPI subjects experienced a decrease of more than 10% but less than 20% in FEV 1 percent predicted (Table 11).
  • Three of the six TPI subjects (subject 02/507 at the TPI 3 ⁇ 28 mg dose and subjects 01/415 and 08/406 at the TPI 4 ⁇ 28 mg dose) experienced cough or cough aggravated within minutes after dosing.
  • TPI subjects 60.6%) than TOBI subjects (30.0%) experienced treatment-emergent AEs during or after treatment.
  • the percent of subjects with any AE was similar among the TPI dose levels (45% to 69%); sample sizes were too small to determine whether a trend was present for increasing any-AE incidence with increasing TPI dose. All treatment-emergent AEs were mild or moderate in intensity.
  • TPI 4 ⁇ 28 mg subject experienced two SAEs (moderate cough and sputum increased indicative of an exacerbation of CF lung disease) that led to hospitalization on the eighth day after the single-dose study treatment was administered; neither of these SAEs was considered related to TPI treatment.
  • Another TPI 4 ⁇ 28 mg subject experienced moderate, probably-related cough aggravated, dysgeusia, and lacrimation increased that caused study drug administration to be interrupted and then stopped; the subject then withdrew consent and was withdrawn from the study.
  • AEs experienced by the largest number of TPI subjects were cough or cough aggravated (13 of 66 subjects 19.7%); dysgeusia (11 subjects, 16.7%); pharyngitis, haemoptysis, and rhinorrhea (4 subjects, 6.1% each); sputum increased, crackles lung, lacrimation increased, abdominal pain upper, dizziness, headache NOS, and throat irritation (3 subjects, 4.5% each).
  • the incidence of cough, cough aggravated, and dysgeusia increased slightly with increasing TPI dose.
  • TPI Single dose administration of TPI results in a more efficient delivery of tobramycin than TOBI® Tobramycin Solution for Inhalation, while maintaining similar tobramycin pharmacokinetics.
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