11 DESCRIPTION
TOBI Podhaler consists of a dry powder formulation of tobramycin for oral inhalation only with the Podhaler device. The inhalation powder is filled into clear, colorless hypromellose capsules.

Each clear, colorless hypromellose capsule contains a spray dried powder of 28 mg of tobramycin active ingredient with 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), calcium chloride, and sulfuric acid (for pH adjustment).

The active component of TOBI Podhaler is tobramycin. Tobramycin is an aminoglycoside antibiotic. Its chemical name is O-3-amino-3-deoxy-α-D-glucopyranosyl-(1→4)-O-[2,6-diamino-2,3,6-trideoxy-α-D-ribo-hexopyranosyl-(1→6)]-2-deoxy-L-streptamine; its structural formula is:

Tobramycin has a molecular weight of 467.52, and its empirical formula is C18H37N5O9. Tobramycin is a white to almost white powder; visually free from any foreign contaminants. Tobramycin is freely soluble in water, very slightly soluble in ethanol, and practically insoluble in chloroform and ether.

The Podhaler device is a plastic device used to inhale the dry powder contained in the TOBI Podhaler capsule. Under standardized in vitro testing at a fixed flow rate of 60 L/min and volume of 2 L for 2 seconds, the Podhaler device has a target delivered dose 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 fr