Phase II studies of nebulised Arikace in CF patients withPseudomonas aeruginosainfection

Abstract

RationaleArikace is a liposomal amikacin preparation for aerosol delivery with potent Pseudomonas aeruginosa killing and prolonged lung deposition.ObjectivesTo examine the safety and efficacy of 28 days of once-daily Arikace in cystic fibrosis (CF) patients chronically infected with P aeruginosa.Methods105 subjects were evaluated in double-blind, placebo-controlled studies. Subjects were randomised to once-daily Arikace (70, 140, 280 and 560 mg; n=7, 5, 21 and 36 subjects) or placebo (n=36) for 28 days. Primary outcomes included safety and tolerability. Secondary outcomes included lung function (forced expiratory volume at one second (FEV1)), P aeruginosa density in sputum, and the Cystic Fibrosis Quality of Life Questionnaire—Revised (CFQ-R).ResultsThe adverse event profile was similar among Arikace and placebo subjects. The relative change in FEV1 was higher in the 560 mg dose group at day 28 (p=0.033) and at day 56 (28 days post-treatment, 0.093L±0.203 vs −0.032L±0.119; p=0.003) versus placebo. Sputum P aeruginosa density decreased >1 log in the 560 mg group versus placebo (days 14, 28 and 35; p=0.021). The Respiratory Domain of the CFQ-R increased by the Minimal Clinically Important Difference (MCID) in 67% of Arikace subjects (560 mg) versus 36% of placebo (p=0.006), and correlated with FEV1 improvements at days 14, 28 and 42 (p<0.05). An open-label extension (560 mg Arikace) for 28 days followed by 56 days off over six cycles confirmed durable improvements in lung function and sputum P aeruginosa density (n=49).ConclusionsOnce-daily Arikace demonstrated acute tolerability, safety, biologic activity and efficacy in patients with CF with P aeruginosa infection.

Lipid and polymer nanoparticles for drug delivery to bacterial biofilms

“…The results of the phase II clinical trial have been published and showed a durable improvement in lung function and a reduced P. aeruginosa sputum count. [62] Furthermore, Arikace® is also being investigated as a treatment for nontuberculous mycobacterial lung disease (phase II clinical trial) and for non-CF bronchiectasis patients with P. aeruginosa lung infections (phase II clinical trial), which both likely involve biofilm formation. No clinical data are available at this moment.…”

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

“…Amikacin concentrations in sputum were about 45-fold higher upon aerosolized administration of 500 mg of a liposomal formulation than after parenteral administration of 30 mg/kg of body weight; mean sputum concentrations increased ϳ3-to 5-fold from day 1 to day 14 (170,171). In supplemental material published previously (158), it was reported that mean serum concentrations as low as 1.29 g/liter and mean sputum concentrations of 2,286 g/g were recorded following aerosolized administration of 560 mg (171).…”

“…In supplemental material published previously (158), it was reported that mean serum concentrations as low as 1.29 g/liter and mean sputum concentrations of 2,286 g/g were recorded following aerosolized administration of 560 mg (171).…”

“…High sputum concentrations were achieved upon aerosolized administration; sputum concentrations increased dose proportionally from 383 to 879 to 985 mg/kg following aerosol delivery of 75, 150, and 225 mg. Systemic exposure was low but occurred rapidly (Table 2) (171)(172)(173)(174)(175)(176)(177).…”

Inhaled Antibiotics for Lower Airway Infections

“…Based on in vitro studies, liposomes demonstrate excellent penetration into CF sputum and P. aeruginosa biofilms (63). A phase 2 clinical trial in CF supported preliminary pharmacokinetics, safety, and efficacy of this therapy; we are awaiting the results of a European/Canadian comparator trial (64).…”