Use of Aerosolized Antibiotics in Patients With Cystic Fibrosis: Pharmacokinetics
Extrapolating the Ideal Dosage of Aerosolized Tobramycin: To determine the ideal dosage of aerosolized antibiotics requires extrapolation from the following: (1) in vitro measurements of sputum-tobramycin interaction; (2) assumptions made about the physical characteristics of the nebulizer and the amount of antibiotics reaching the site of infection; and (3) the concentration of antimicrobial agent needed to inhibit most strains of P aeruginosa. The 600-mg dose studied sought to achieve a minimum peak sputum tobramycin concentration of 400 ^g/g of sputum in every patient. This calculation was based on the “worst case” sputum and an MIC for tobramycin of 4 ^g/mL for susceptible P aeruginosa. The median peak sputum concentration achieved with the 600-mg dose was 4,000 ^g/g of sputum, indicating that many patients actually received more antibiotic than needed to kill P aeruginosa. These observations led to the 300-mg twice-daily dose of preservative-free tobramycin used in the phase III trials.
Absorption of Bioavailability of Inhaled Tobramycin: Absorption of tobramycin from the respiratory tract, following administration by inhalation, is a complex phenomenon. For most nebulizer systems, it is estimated that approximately 10% of the mass of drug initially nebulized is deposited in the lungs and the remaining 90% either remains in the nebulizer, is impacted on the oropharynx and swallowed, or is exhaled into the atmosphere.2 Thus, describing the relationship between administered doses and serum tobramycin concentrations is complicated by the inability to measure the actual dose of drug delivered to the site of absorption in different animal test systems or in humans. In a pharmacokinetic evaluation of aerosolized tobramycin (400- or 600-mg dosages) delivered by ultrasonic nebulizer, 9 of 10 patients studied had peak serum tobramycin concentrations < 1 ^g/mL. However, the peak concentration for one patient was > 20 ^g/mL. The authors of this study suggest obtaining a blood sample 1 to 2 h following administration of nebulized tobramycin to monitor for tobramycin systemic absorption. Source
However, other studies of aerosolized tobramycin have not noted similar elevations in peak serum concentrations. Absolute bioavailability was not directly measured in the preservative-free tobramycin 300-mg bid phase III trials but was estimated to be 11.7%. Peak serum concentrations from the 300-mg preservative-free tobramycin trials are comparable to those reported in the literature and are significantly lower than reported systemic concentrations following parenteral administration of therapeutic doses of tobramycin (Table 1).
Table 1—Tobramycin Serum and Sputum Concentrations Following Aerosol and Parenteral Administration
|Source||No. of Patients||Nebulizer||Dosage, mg/Route||Mean Peak Serum Concentration, |xg/mL||Mean Peak Sputum Concentration, ^g/g|
|Eisenberg et al||60||Pari LC||300 mg bid/aerosol||0.57 ± 0.38||687 ± 663|
|60||Sidestream*||300 mg bid/aerosol||0.74 ± 0.43||489 ± 402|
|p = 0.02|
|Ramsey et al||247||Pari LC Plus||300 mg bid/aerosol||1.01 ± 0.57||1199.2|
|Mendelman et al||10||NAt||6.0-10.8 mg/kg/IV||7.5||82|