ose of 102 mg of tobramycin from the mouthpiece (4 capsules per dose). Peak inspiratory flow rate and inhaled volumes were explored in 96 cystic fibrosis patients aged 6 years and older. Older patients with significant disease progression and associated decreases in forced expiratory volume (FEV1) and younger patients with inhaled volumes < 1 L were able to generate inspiratory flow rates and volumes required to receive their medication when following the instructions for use. However, no pediatric patients aged 6 to 10 years with FEV1 less than 40% predicted were eva luated.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Tobramycin is an aminoglycoside antibiotic [see Clinical Pharmacology (12.4)].
12.3 Pharmacokinetics
Absorption
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.
Serum concentrations
After inhalation of a 112 mg single dose (4 x 28 mg capsules) of TOBI Podhaler in cystic fibrosis patients, the maximum serum concentration (Cmax) of tobramycin was 1.02 ± 0.53 µg/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 µg/mL and median Tmax was 1 hour. The extent of systemic exposure (AUC0-12) was also similar: 4.6 ± 2.0 µg∙h/mL following the 112 mg TOBI Podhaler dose and 4.8 ± 2.5 µg∙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 µg/mL to 1.99 ± 0.59 µg/mL (mean ± SD).
Sputum concentrations
After inhalation of a 112 mg single dose (4 x 28 mg capsules) of TOBI Podhaler in cystic fibrosis patients, sputum Cmax of tobramycin was 1048 ± 1080 µg/g (mean ± SD). In comparison, after inhalation of a single 300 mg dose of TOBI, sputum Cmax was 737 ± 1028 µg/g. The variability in pharmacokinetic parameters was higher in sputum as compared to serum.
Distribution
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 CF patient.
Binding of tobramycin to serum proteins is negligible.
Metabolism
Tobramycin is not metabolized and is primarily excreted unchanged in the urine.
Elimination
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 i
