Table 1 Overview of the research pathway with the study components aimed at characterising the pharmacokinetics of nebulised tobramycin
Research pathway | ||||
|---|---|---|---|---|
Study | 1. In vitro particle sizing and inhaled mass study | 2. In vivo lung distribution study | 3. In vitro microdialysis recovery study | 4. In vivo lung microdialysis study |
Aims | Describing and comparing the aerosol characteristics of two formulations of tobramycin | Comparing lung distribution of i.v. vs nebulised radiolabelled tobramycin 400Â mg | Comparing relative recovery of vancomycin and tobramycin with microdialysis | Comparing ISF, ELF and blood concentrations of i.v. vs nebulised tobramycin 400Â mg |
Design | In vitro simulated adult mechanical ventilation using • Laser diffraction • Inhaled mass | Mechanically ventilated healthy ovine model | In vitro study using simulated in vivo conditions | Mechanically ventilated healthy ovine model |
Materials and methods | • Size 9.0 mm I.D. ETT and tracheostomy tube • 4 ml tobramycin 100 mg/ml (400 mg) and 40 mg/ml (160 mg) • Vibrating mesh nebuliser just proximal to the Y- piece • Triplicate experiments | • Technetium-99m-labelled tobramycin 400 mg • i.v. administration (n = 1) • Nebulisation (n = 1) • CT scan to derive lung outline • Gamma camera scanning—dorsal, ventral, bilateral • Tissue and blood sampling | • Vancomycin 5 μg/ml • Tobramycin 5 μg/ml • In 50 ml FFP solution and constant stirrer • Perfusate flow rates 1, 1.5 and 2 μl/min • Sample collection every 20 min for 100 min (n = 5) • Triplicate experiments | • Bilateral thoracotomy approach for insertion of microdialysis catheters • i.v. tobramycin 400 mg (n = 1) • Nebulised tobramycin 400 mg (n = 1) • Bronchoalveolar lavage (1 and 6 h) • Intravascular microdialysis • Sample collection every 20 min for 8 h (n = 24) |
Analysis | Particle size distribution parameters: • dv10 (μm) • dv50 (μm) • dv90 (μm) • FPF (%) Inhaled mass parameters: • Inhaled drug percentage (%) • Lung dose (mg) | • P/C ratio • Dorsal: ventral ratio • Right: left lung ratio • Upper: middle: lower lung zone • Quantitative analysis in the lung, liver, kidney, blood and urine specimens | • Relative recovery values for each of the flow rates | • ELF concentration and PK • ISF concentration and PK • Plasma concentration and PK |