"The U.S. Food and Drug Administration today approved Rapamune (sirolimus), to treat lymphangioleiomyomatosis (LAM), a rare, progressive lung disease that primarily affects women of childbearing age. This is the first drug approved to treat the di"...
Mechanism Of Action
Tobramycin is an aminoglycoside antibiotic [see Microbiology].
TOBI Podhaler contains tobramycin, a cationic polar molecule that does not readily cross epithelial membranes. TOBI Podhaler is specifically formulated for administration by oral inhalation. The systemic exposure to tobramycin after inhalation of TOBI Podhaler is expected to result from pulmonary absorption of the dose fraction delivered to the lungs as tobramycin and is not absorbed to any appreciable extent when administered via the oral route.
After inhalation of a 112 mg single dose (4 times 28 mg capsules) of TOBI Podhaler in cystic fibrosis patients, the maximum serum concentration (Cmax) of tobramycin was 1.02 ± 0.53 mcg/mL (mean ± SD) and the median time to reach the peak concentration (Tmax) was 1 hour. In comparison, after inhalation of a single 300 mg dose of TOBI, Cmax was 1.04 ± 0.58 mcg/mL and median Tmax was 1 hour. The extent of systemic exposure (AUC0-12) was also similar: 4.6 ± 2.0 mcg·h/mL following the 112 mg TOBI Podhaler dose and 4.8 ± 2.5 mcg·h/mL following the 300 mg TOBI dose. At the end of a 4-week dosing cycle of TOBI Podhaler (112 mg twice-daily), the maximum serum concentration of tobramycin 1 hour after dosing ranged from 1.48 ± 0.69 mcg/mL to 1.99 ± 0.59 mcg/mL (mean ± SD).
After inhalation of a 112 mg single dose (4 times 28 mg capsules) of TOBI Podhaler in cystic fibrosis patients, sputum Cmax of tobramycin was 1048 ± 1080 mcg/g (mean ± SD). In comparison, after inhalation of a single 300 mg dose of TOBI, sputum Cmax was 737 ± 1028 mcg/g. The variability in pharmacokinetic parameters was higher in sputum as compared to serum.
A population pharmacokinetic analysis for TOBI Podhaler in cystic fibrosis patients estimated the apparent volume of distribution of tobramycin in the central compartment to be 85.1 L for a typical cystic fibrosis (CF) patient.
Binding of tobramycin to serum proteins is negligible.
Tobramycin is not metabolized and is primarily excreted unchanged in the urine.
Tobramycin is eliminated from the systemic circulation primarily by glomerular filtration of the unchanged compound. Systemically absorbed tobramycin following TOBI Podhaler administration is also expected to be eliminated principally by glomerular filtration.
The apparent terminal half-life of tobramycin in serum after inhalation of a 112 mg single dose of TOBI Podhaler was approximately 3 hours in cystic fibrosis patients and consistent with the half-life of tobramycin after TOBI inhalation.
A population pharmacokinetic analysis for TOBI Podhaler in cystic fibrosis patients aged 6 to 58 years estimated the apparent serum clearance of tobramycin to be 14.5 L/h. No clinically relevant covariates that were predictive of tobramycin clearance were identified from this analysis.
Mechanism of Action
Tobramycin is an aminoglycoside antimicrobial produced by Streptomyces tenebrarius. It acts primarily by disrupting protein synthesis leading to altered cell membrane permeability, progressive disruption of the cell envelope, and eventual cell death.
Tobramycin has in vitro activity against Gram-negative bacteria including P. aeruginosa. It is bactericidal in vitro at peak concentrations equal to or slightly greater than the minimum inhibitory concentration (MIC).
Interpretive criteria for inhaled antibacterial products are not defined. The in vitro antimicrobial susceptibility test methods used to determine the susceptibility for parenteral tobramycin therapy can be used to monitor the susceptibility of P. aeruginosa isolated from cystic fibrosis patients.1,2,3 The relationship between in vitro susceptibility test results and clinical outcome with TOBI Podhaler therapy is not clear. A single sputum sample from a cystic fibrosis patient may contain multiple morphotypes of P. aeruginosa and each morphotype may require a different concentration of tobramycin to inhibit its growth in vitro. Patients should be monitored for changes in tobramycin susceptibility.
Development of Resistance
In clinical studies, some increases from baseline to the end of the treatment period were observed in the tobramycin MIC for P. aeruginosa morphotypes. In general, a higher percentage of patients treated with TOBI Podhaler had increases in tobramycin MIC compared with placebo or patients treated with TOBI inhalation solution.
The clinical significance of changes in MICs for P. aeruginosa has not been clearly established in the treatment of cystic fibrosis patients.
Some emerging resistance to aztreonam, ceftazidime, ciprofloxacin, imipenem, or meropenem were observed in the TOBI Podhaler clinical trials. As other anti-pseudomonal antibiotics were concomitantly utilized in many patients in the clinical trials, the association with TOBI Podhaler is not clear.
No trends were observed in the isolation of treatment-emergent bacterial respiratory pathogens (Burkholderia cepacia, Stenotrophomonas maltophilia, Staphylococcus aureus, and Achromobacter xylosoxidans).
The Phase 3 clinical development program included two placebo-controlled studies (Studies 2 and 3) and one open-label study (Study 1), which randomized and dosed 157 and 517 patients, respectively, with a clinical diagnosis of cystic fibrosis, confirmed by quantitative pilocarpine iontophoresis sweat chloride test, well-characterized disease causing mutations in each CFTR gene, or abnormal nasal transepithelial potential difference characteristic of cystic fibrosis.
In the placebo-controlled studies, all patients were aged between 6 and 21 years old and had an FEV1 at screening within the range of 25% to 80% (inclusive) of predicted normal values for their age, sex, and height based upon Knudson criteria. In addition, all patients were infected with P. aeruginosa as demonstrated by a positive sputum or throat culture (or bronchoalveolar lavage) within 6 months prior to screening, and also in a sputum culture taken at the screening visit. Among the 76 patients treated with TOBI Podhaler, 37% were males and 63% were females. Thirty-six patients were between 6 and 12 years of age, and 40 patients were between 13 and 21 years of age. Patients had a mean baseline FEV1 of 56% of predicted normal value.
In both studies, > 90% of patients received concomitant therapies for cystic fibrosis-related indications. The most frequently used other antibacterial drugs (any route of administration) were azithromycin, ciprofloxacin, and ceftazidime. Consistent with the population of cystic fibrosis patients, the most frequently used concomitant medications included oral pancreatic enzyme preparations, mucolytics (especially dornase alfa), and selective β2-adrenoreceptor agonists.
Study 2 was a randomized, 3-cycle, 2-arm trial. Each cycle comprised of 28 days on treatment followed by 28 days off treatment. The first cycle was double-blind, placebo-controlled with eligible patients randomized 1:1 to TOBI Podhaler (4 times 28 mg capsules twice-daily) or placebo. Upon completion of the first cycle, patients who were randomized to the placebo treatment group received TOBI Podhaler for Cycles 2 and 3. The total treatment period was 24 weeks.
A total of 95 patients were randomized into Study 2 and received TOBI Podhaler (n=46) or placebo (n=49) in Cycle 1. All patients were less than 22 years of age (mean age 13.3 years) and had not received inhaled antipseudomonal antibiotics within four months prior to screening; 56% were female and 84% were Caucasian. This study was stopped early for demonstrated benefit and the primary analysis used the set of patients included in the interim analysis (n=79); 16 patients did not have data on the primary endpoint at that time. Of the 79 patients included in the interim analysis, 18 patients were excluded due to a failure to meet spirometry quality review criteria as determined by an external review panel. This resulted in a total of 61 patients, 29 in the TOBI Podhaler arm and 32 in the placebo arm, who were included in the primary analysis.
In the primary analysis, TOBI Podhaler significantly improved lung function compared with placebo as measured by the relative change in FEV1 % predicted from baseline to the end of Cycle 1 dosing. This analysis adjusted for the covariates of baseline FEV1 % predicted, age, and region, and imputed for missing data. Treatment with TOBI Podhaler and placebo resulted in relative increases in FEV1 % predicted of 12.54% and 0.09%, respectively (LS mean difference = 12.44%; 95% CI: 4.89, 20.00; p=0.002). Analysis of absolute changes in FEV1 % predicted showed LS means of 6.38% for TOBI Podhaler and -0.52% for placebo with a difference of 6.90% (95% CI: 2.40, 11.40). Improvements in lung function were achieved during the subsequent cycles of treatment with TOBI Podhaler, although the magnitude was reduced (Figure 1).
The percentage of patients using new antipseudomonal antibiotics in Cycle 1 was greater in the placebo treatment group (18.4%) compared with the TOBI Podhaler treatment group (13.1%). During the first cycle, 8.7% of TOBI Podhaler patients and 10.2% of placebo patients were treated with parenteral antipseudomonal antibiotics. In Cycle 1, two patients (4.4%) in the TOBI Podhaler treatment group required respiratory-related hospitalizations, compared with six patients (12.2%) in the placebo treatment group.
Figure 1 – Study 2: Mean Relative Change in FEV1 %
Predicted from Baseline in Cycles 1 to 3 by Treatment Group
Study 3 was a randomized, double-blind, placebo-controlled trial, similar in design to Study 2. Eligible patients were randomized 1:1 to receive TOBI Podhaler (4 times 28 mg capsules twice-daily) or placebo for one cycle (28 days on-treatment and 28 days off-treatment).
A total of 62 patients were randomized into Study 3 and allocated to TOBI Podhaler (n=32) or placebo (n=30). All patients were less than 22 years of age (mean age 12.9 years) and had not received inhaled antipseudomonal antibiotics within 4 months prior to screening; 64.5% were female and 98.4% were Caucasian.
In this study, the results were not statistically significant for the primary lung function endpoint when adjusting for the covariates of age ( < 13 years, ≥ 13 years) and FEV1 % predicted at screening ( < 50%, ≥ 50%) and imputing for missing data. Improvement in lung function for TOBI Podhaler compared with placebo was evaluated using the relative change in FEV1 % predicted from baseline to the end of Cycle 1 dosing. Treatment with TOBI Podhaler (8.19%) compared to placebo (2.27%) failed to achieve statistical significance in relative change in FEV1 % predicted (LS mean difference = 5.91%; 95% CI: -2.54, 14.37; p=0.167). Analyses of absolute changes in FEV1 % predicted showed LS means of 4.86% for TOBI Podhaler and 0.48% for placebo with a difference of 4.38% (95% CI:-0.17, 8.94).
Study 1 was a randomized, open-label, active-controlled parallel arm trial. Eligible patients were randomized 3:2 to TOBI Podhaler (4 times 28 mg capsules twice-daily) or TOBI (300 mg/5 mL twice-daily). Treatment was administered for 28 days, followed by 28 days off therapy (one cycle) for three cycles. The total treatment period was 24 weeks. The time to administer a dose of TOBI Podhaler (10th to 90th percentiles) ranged from 2 to 7 minutes at the end of the dosing period for Cycle 1, and 2 to 6 minutes at the end of the dosing period for Cycle 3.
A total of 517 patients were randomized in Study 1 and received TOBI Podhaler (n=308) or TOBI (n=209). Patients were predominantly 20 years of age or older (mean age 25.6 years) with no inhaled antipseudomonal antibiotic use within 28 days prior to study drug administration; 45% were female and 91% were Caucasian.
The primary purpose of Study 1 was to evaluate safety. Interpretation of efficacy results in Study 1 is limited by several factors including open-label design, testing of multiple secondary endpoints, and missing values for the outcome of FEV1 % predicted. The number (%) of patients with missing values for FEV1 % predicted at Weeks 5 and 25 in the TOBI Podhaler treated group were 40 (13.0%) and 86 (27.9%) compared to 15 (7.2%) and 40 (19.1%) in the TOBI treated group. Using imputation of the missing data, the mean differences (TOBI Podhaler minus TOBI) in the percent relative change from baseline in FEV1 % predicted at Weeks 5 and 25 were -0.87 (95% CI: -3.80, 2.07) and 1.62 (95% CI: -0.90, 4.14), respectively.
1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically – Ninth Edition; Approved Standard. CLSI Document M7-A9. CLSI, 950 West Valley Rd., Suite 2500, Wayne, PA 19087, 2012.
2. CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard – 11th ed. CLSI document M02-A11. CLSI, 2012.
3. CLSI. Performance Standards for Antimicrobial Susceptibility Testing; 22nd Informational Supplement. CLSI document M100-S22. CLSI, 2012
Last reviewed on RxList: 10/14/2015
This monograph has been modified to include the generic and brand name in many instances.
Additional TOBI Podhaler Information
Report Problems to the Food and Drug Administration
Find out what women really need.