IntroductionThe Amikacin Inhale System (BAY41-6551, NKTR-061) is an integrated drug-device combination in clinical development for adjunctive treatment of Gram-negative pneumonia in intubated, mechanically ventilated patients. The Amikacin Inhale System consists of a disposable, proprietary vibrating mesh nebulizer used to aerosolize a specially formulated amikacin inhalation solution (400mg, 3.2 mL of 125 mg/mL, b.i.d. for 10 days). It has been designed for use in two configurations: one for intubated patients (on-vent configuration, Figure 1), and one for patients extubated prior to the end of their 10-day course of therapy (handheld configuration, Figure 2). Results from Phase II studies indicated that high drug concentrations were achieved in both tracheal aspirates and epithelial lining fluid (ELF) with low systemic concentration and no observed renal toxicity [1-3]. The Amikacin Inhale System was modified between the Phase II and III clinical trials to facilitate commercial manufacturing. This study reports the in vitro estimated lung dose (ELD) obtained using the Phase III Amikacin Inhale System in both on-vent and handheld configurations.

MethodThe study parameters for the in vitro on-vent and handheld configurations are presented in Table 1.**

Table 1 In vitro study parameters: on-vent and handheld configurations

Test method On-vent (Figure 3) Handheld (Figure 4)

Ventilator Puritan Bennett 840 Harvard Ventilator

Ventilator settingTV: 500 mL; RR: 15 bpm; PIFR: 40 Lpm; I:E: 1:2

TV: 500 mL; RR: 15 bpm; I:E: 1:2

DoseAmikacin inhalation solution (3.2 mL at 125 mg/mL)

Amikacin inhalation solution (3.2 mL at 125 mg/mL)

Nebulizer tested

81 nebulizers with: VMD: 4.4 ± 0.5 µm and output rate: 0.24 ± 0.05 mL/min

A separate 81 nebulizers with: VMD: 4.4 ± 0.5 µm and output rate: 0.24 ± 0.05 mL/min

Mode of aerosolization

Phasic, breath-synchronized

Continuous

Compartments analyzed

Inspiratory and expiratory filters, nebulizer, trap, T-piece

Inspiratory and expiratory filters, nebulizer, mouthpiece, handheld chamber

ELD quantified by HPLC [% of nominal]

Amount collected in inspiratory filter

Amount collected in inspiratory filter x FPF <5.0 µm

Results and DiscussionThe performance characteristics for the Amikacin Inhale System in the on-vent and handheld configurations are shown in Table 2. For the same dose of amikacin, nebulization time for the handheld

configuration (15 ± 5 minutes) was shorter than that in the on-vent configuration (36 ± 16 minutes) due to the difference in operating mode.

Comparable ELDs were observed for on-vent and handheld configurations (Figures 5 and 6).

Mean ELD was 50% ± 9% of nominal dose for on-vent configuration and was comparable with 49% ± 11% for handheld configuration (Table 2).

ELD increased as volume median diameter (VMD) decreased and dosing administration time increased because droplets with larger VMD and higher output rates had greater tendency to be trapped within the system due to impaction.

Data were analyzed using a least-squares method (JMP 8.0, Cary NC [4]).

Lower and upper (± standard error) 95% confidence limits defined the minimum and maximum ELD, respectively, for a given combination of VMD and dosing time (Figures 7 and 8).

Minimum achievable ELD was 35–58% of nominal dose (Figure 7) for the on-vent configuration and 35–64% of nominal dose for the handheld configuration (Figure 8).

Based on Phase I and II clinical data [1-3,5], it is likely that the ELDs for the Amikacin Inhale System in either configuration will exceed the MIC of Gram-negative respiratory tract pathogens in ICU patients with pneumonia.

Table 2 Measured/calculated parameters for on-vent and handheld configurations (mean ± SD)

Parameters On-vent Handheld

VMD [µm] 4.4 ± 0.5 4.4 ± 0.5

Output rate [mL/min] 0.24 ± 0.05 0.24 ± 0.05

Dosing administration time [min] 36 ± 16 15 ± 5

ELD [% of nominal] 50 ± 9 49 ± 11

ConclusionsThe study results demonstrated that the Amikacin Inhale System can achieve highly efficient delivery of amikacin in both configurations: on-vent with breath synchronization and handheld with continuous nebulization. Comparable ELDs were obtained in both configurations, indicating that no dose adjustment was required when switching from the on-vent to the handheld configuration.

References1. Luyt CE et al. J Aerosol Med Pulm Drug Del 2011;24:183-190. 2. Luyt CE et al. Crit Care 2009;R200.3. Niederman MS et al. Int Care Med 2012;38:263-271.4. JMP version 8. Statistical Software, SAS, Cary, NC. 5. Fink J et al. Am J Respir Crit Care Med 2008;177:A530.

* Brown shell on nebulizer reservoir is the blinding for Phase III clinical trials.** All in vitro work was conducted at Novartis Pharmaceuticals, California and funded by Nektar

Therapeutics, California.

In vitro efficiency of the Amikacin Inhale System, a novel integrated drug-device delivery systemN. Kadrichu1; S. Boc1; K. Corkery1; P. Challoner21Novartis Pharmaceuticals, San Carlos, United States, 2Nektar Therapeutics, San Francisco, United States.

Figure 1. On-vent configuration* Figure 2. Handheld configuration*

Figure 3. In vitro on-vent configuration Figure 4. In vitro handheld configuration*

Figure 7. Minimum on-vent ELD vs dosing time and VMD

Figure 8. Minimum handheld ELD vs dosing time and VMD

Figure 5. On-vent ELD as a function of dosing time and VMD

Figure 6. Handheld ELD as a function of dosing time and VMD

Poster A384 presented at ISICEM 2013, March 19-22, Brussels

VMD: volume median diameter; ELD: estimated lung dose.

TV: tidal volume; RR: respiratory rate; PIFR: peak inspiratory flow rate; I:E: inspiratory:expiratory ratio; VMD: volume median diameter; ELD: estimated lung dose; FPF: fine particle fraction; HPLC: high performance liquid chromatography.

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