Pharmacokinetics and Safety of MP-376 (Levofloxacin Inhalation Solution) in Cystic Fibrosis Subjects

Abstract

The pharmacokinetics and tolerability of nebulized MP-376 (levofloxacin inhalation solution [Aeroquin]) were determined in cystic fibrosis (CF) subjects. Ten CF subjects received single 180-mg doses of two formulations of MP-376, followed by a multiple-dose phase of 240 mg once daily for 7 days. Serum and expectorated-sputum samples were assayed for levofloxacin content. Safety was evaluated following the single-and multiple-dose study phases. Nebulized MP-376 produced high concentrations of levofloxacin in sputum. The mean maximum plasma concentration (C max ) ranged between 2,563 and 2,932 mg/liter for 180-mg doses of the 50-and 100-mg/ml formulations, respectively. After 7 days of dosing, the mean C max for the 240-mg dose was 4,691 mg/liter. The mean serum levofloxacin C max ranged between 0.95 and 1.28 for the 180-mg doses and was 1.71 for the 240-mg dose. MP-376 was well tolerated. Nebulized MP-376 produces high sputum and low serum levofloxacin concentrations. The pharmacokinetics, safety, and tolerability were similar for the two formulations. MP-376 240 mg (100 mg/ml) is being advanced into late-stage clinical development.Patients with cystic fibrosis (CF) suffer from recurrent and chronic infections of the lower respiratory tract. Pseudomonas aeruginosa in particular has been implicated as a major risk factor for declining lung function and associated morbidity and mortality in CF patients (5). Aerosol delivery of an antibiotic directly to the lung increases the local concentration of the drug at the site of infection, thereby enhancing bacterial killing and reducing the selection of resistance compared to the outcomes of systemic administration. Currently, a tobramycin solution for inhalation (TOBI; Novartis Pharmaceuticals, East Hanover, NJ) and aztreonam lysine for inhalation (Cayston; Gilead Pharmaceuticals, Seattle, WA) are the two aerosol antibiotics approved in the United States for the management of CF patients with P. aeruginosa. For a number of reasons, including decreased efficacy, drug intolerance, new emerging pathogens, and inconvenient dosing regimens, there is a need for alternative inhaled therapies to treat CF patients with pulmonary infections caused by P. aeruginosa and other bacteria.Levofloxacin is a fluoroquinolone antibiotic with potent activity against key pathogens in CF patients, including P. aeruginosa. Unlike tobramycin, levofloxacin's activity is not reduced in CF sputum (8). In addition, levofloxacin has greater antimicrobial activity than tobramycin and aztreonam in biofilms produced by P. aeruginosa (8). Extensive in vitro and animal pharmacokinetic-pharmacodynamic studies, as well as both retrospective and prospective clinical studies, have established a clear link between the exposure to fluoroquinolones and clinical response (1). While not conducted in patients with CF, studies with levofloxacin show that bacterial killing and clinical efficacy is linked to the plasma area under the concentrationtime curve (AUC)/MIC ratio or maximum plasma concentration (C max )/MIC ...

A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients

“…Both the uniqueness of mechanistic class and recognized utility of fluoroquinolones in treating CF airway infection make them an attractive candidate for inhaled CF therapy. APT-1026 (levofloxacin inhalation solution, LIS; also formerly known as MP-376) 13 is a formulation of a fluoroquinolone intended for inhaled use in chronic maintenance therapy. We describe the results of a placebo-controlled study designed to evaluate the efficacy and safety of LIS in individuals with CF and chronic P. aeruginosa infection who had previously used inhaled tobramycin.…”

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

“…Ciprofloxacin sputum and ELF (151)(152)(153)(154)(155)(156). However, its sputum concentrations measured following aerosolized administration surpass lung tissue or ELF concentrations achieved following oral or intravenous administration by 100-to 1,000-fold, reaching sputum concentrations of almost 3,000 mg/liter (157).…”

Stenotrophomonas maltophilia: an Emerging Global Opportunistic Pathogen

“…Observations of CF subjects receiving nebulized formulations of MP-376 (levofloxacin inhalation solution; Aeroquin) at a dose of 180 mg followed by 7 days of daily treatment doses of 240 mg demonstrated high sputum and low serum levofloxacin concentrations. Patients tolerated the MP-376 formulations well, with no serious adverse events reported and no patients excluded during the study due to an adverse event (121). Clinical trials using MP-376 are needed to assess the efficacy and tolerance of this antibiotic in CF subjects with S. maltophilia infections.…”

“…That study suggested the potential for the use of levofloxacin as an aerosolized antibiotic in CF patient infections. An additional attractive feature of levofloxacin is the higher maximum concentration of the drug (C max )/MIC and area under the curve (AUC)/MIC values obtained through aerosolized delivery, in contrast to those values obtained for intravenous or oral delivery (121). Observations of CF subjects receiving nebulized formulations of MP-376 (levofloxacin inhalation solution; Aeroquin) at a dose of 180 mg followed by 7 days of daily treatment doses of 240 mg demonstrated high sputum and low serum levofloxacin concentrations.…”