Safety, Tolerability, and Pharmacokinetic Properties of Intravenous Delafloxacin After Single and Multiple Doses in Healthy Volunteers

Hoover, Randall; Hunt, Thomas L.; Benedict, Michael; Paulson, Susan K.; Lawrence, Laura; Cammarata, Sue; Sun, Eugene

doi:10.1016/j.clinthera.2015.11.019

Cited by 48 publications

(58 citation statements)

References 13 publications

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“…and intravenous (i.v.) formulations have been developed with promising pharmacokinetic (PK) and efficacy results (1,2). Delafloxacin has a broad spectrum of activity that includes drug-resistant Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae (3)(4)(5)(6)(7).…”

mentioning

confidence: 99%

In Vivo Pharmacodynamic Target Assessment of Delafloxacin against Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae in a Murine Lung Infection Model

Lepak

Andes

2016

Antimicrob Agents Chemother

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cDelafloxacin is a broad-spectrum anionic fluoroquinolone under development for the treatment of bacterial pneumonia. The goal of the study was to determine the pharmacokinetic/pharmacodynamic (PK/PD) targets in the murine lung infection model for Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae. Four isolates of each species were utilized for in vivo studies: for S. aureus, one methicillin-susceptible and three methicillin-resistant isolates; S. pneumoniae, two penicillinsusceptible and two penicillin-resistant isolates; K. pneumoniae, one wild-type and three extended-spectrum beta-lactamaseproducing isolates. MICs were determined using CLSI methods. A neutropenic murine lung infection model was utilized for all treatment studies, and drug dosing was by the subcutaneous route. Single-dose plasma pharmacokinetics was determined in the mouse model after administration of 2.5, 10, 40, and 160 mg/kg. For in vivo studies, 4-fold-increasing doses of delafloxacin (range, 0.03 to 160 mg/kg) were administered every 6 h (q6h) to infected mice. formulations have been developed with promising pharmacokinetic (PK) and efficacy results (1, 2). Delafloxacin has a broad spectrum of activity that includes drug-resistant Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae (3-7). Previous clinical studies in patients with acute bacterial skin and skin structure infections (ABSSIs) have demonstrated potency and efficacy, especially with respect to S. aureus (8,9).Pneumonia is one of the most common infectious diseases encountered worldwide and remains a significant cause of morbidity and mortality (10). The major pathogen of community-acquired pneumonia (CAP) continues to be S. pneumoniae despite major advances in vaccination development and administration to at-risk populations. In the hospital setting, S. aureus and Gram-negative bacteria are more commonly encountered and are frequently drug resistant (11).Staphylococcus aureus is particularly challenging due to its inherent pathogenicity and increased prevalence of drug-resistant phenotypes (i.e., methicillin-resistant S. aureus [MRSA]) contributing to serious infections. It is the leading bacterial cause of life-threatening infection due to these attributes (12)(13)(14). For example, in the United States, S. aureus is the most common cause of nosocomial infection and leads to more than 80,000 illnesses and 11,000 deaths yearly (12). Unfortunately, there is a paucity of novel agents to treat MRSA pulmonary infections and even fewer that have oral and i.v. formulation options.The objectives of our experiments were to characterize the in vivo efficacy of delafloxacin using a neutropenic murine lung infection model for three common respiratory tract pathogen groups, including S. aureus, S. pneumoniae, and K. pneumoniae. Specifically, the pharmacokinetic/pharmacodynamic (PK/PD) targets of delafloxacin were examined to provide a framework for

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confidence: 99%

In Vivo Pharmacodynamic Target Assessment of Delafloxacin against Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae in a Murine Lung Infection Model

Lepak

Andes

2016

Antimicrob Agents Chemother

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“…In the phase I study of dose escalation,35 adverse reactions were detected in half or more of the individuals who received a dose of 800 mg or more, while with doses of 300 mg, the AE detected were equivalent to those of the placebo. In the study with oral administration,36 DLX was well tolerated in the range of doses tested (50–1,600 mg).…”

Section: Efficacymentioning

confidence: 99%

“…There are several studies with DLX, dedicated to pharmacokinetic properties, tolerability, effect of concomitant food administration and safety 35,36. After endovenous administration,35 the value of maximum concentration (C max ) increases proportionally with increasing doses within the range from 300 to 1,200 mg.…”

Section: Introductionmentioning

confidence: 99%

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Delafloxacin: design, development and potential place in therapy

Candel¹,

Peñuelas²

2017

DDDT

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Delafloxacin (DLX) is a new fluoroquinolone pending approval, which has shown a good in vitro and in vivo activity against major pathogens associated with skin and soft tissue infections and community-acquired respiratory tract infections. DLX also shows good activity against a broad spectrum of microorganisms, including those resistant to other fluoroquinolones, as methicillin-resistant Staphylococcus aureus. Its pharmacokinetic properties and excellent activity in acidic environments make DLX an alternative in the treatment of these and other infections. In this manuscript, a detailed analysis of this new fluoroquinolone is performed, from its chemical structure to its in vivo activity in recently published clinical trials. Its possible place in the current antimicrobial outlook and in other infectious models is also discussed.

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“…The pharmacokinetic profile of delafloxacin was studied in three phase I clinical trials [16]. The first was a double-blind, randomized, single ascending-dose study in which delafloxacin at the 1-h IV dosages of 300, 450, 600, 750, 900, and 1200 mg was infused to adult healthy volunteers (52 active and 10 placebo).…”

Section: Pharmacokineticsmentioning

confidence: 99%

Clinical and pharmacokinetic drug evaluation of delafloxacin for the treatment of acute bacterial skin and skin structure infections

Bassetti

Pecori

Cojutti

et al. 2017

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: In the era of multi-drug resistant pathogens, the adequate treatment of skin and skin structure infections remains a challenge for clinicians. Delafloxacin, with its broad spectrum against Gram-positive, Gram-negative and anaerobic organisms, represents a new therapeutic option in this setting, especially when coverage of methicillin-resistant Staphylococcus aureus is required in the empirical or targeted approach. Areas covered: In this drug evaluation, the Authors have reviewed the pharmacokinetic and pharmacodynamic characteristics of delafloxacin. In addition, recent data on clinical efficacy and safety from clinical trials have been included. Expert opinion: Delafloxacin represents an attractive therapeutic option due to a broad antimicrobial and favorable pharmacokinetic and pharmacodynamic profile. Several in vitro studies have demonstrated the low potential for resistance selection if used in empirical regimens. Delafloxacin is a promising candidate for the treatment of Gram-positive infections, especially if co-infection with other pathogens is suspected. This is because of the very low MIC of the agent for Gram-positive (including MRSA) and anaerobic bacteria and because of the wide spectrum of activity against Gramnegative organisms. For these interesting microbiological and PK/PD characteristics we expect future uses of this drug in other indications such as diabetic foot infection, osteomyelitis, prosthetic joint infections, abdominal infections and central nervous system infections. ARTICLE HISTORY

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Safety, Tolerability, and Pharmacokinetic Properties of Intravenous Delafloxacin After Single and Multiple Doses in Healthy Volunteers

Abstract: Delafloxacin was well tolerated in healthy volunteers after single and multiple IV doses. The total systemic exposure to IV (300 mg) and oral (450 mg) delafloxacin is comparable, supporting that a switch between the 2 formulations is appropriate.

Cited by 48 publications

References 13 publications

In Vivo Pharmacodynamic Target Assessment of Delafloxacin against Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae in a Murine Lung Infection Model

In Vivo Pharmacodynamic Target Assessment of Delafloxacin against Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae in a Murine Lung Infection Model

Delafloxacin: design, development and potential place in therapy

Clinical and pharmacokinetic drug evaluation of delafloxacin for the treatment of acute bacterial skin and skin structure infections

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