Disposition, metabolism and mass balance of delafloxacin in healthy human volunteers following intravenous administration

McEwen, Andrew; Lawrence, Laura; Hoover, Randy C.; Stevens, Lloyd; Mair, Stuart; Ford, Gill; Williams, D. T.; Wood, Simon

doi:10.3109/00498254.2015.1042946

Cited by 23 publications

(28 citation statements)

References 7 publications

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“…We completed a multiple oral dose study of delafloxacin on the pharmacokinetics of a single oral dose of midazolam, a sensitive substrate for CYP3A . No interaction was found that is consistent with the aforementioned mass balance study and in vitro studies conducted with human liver microsomes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5) (data on file). In contrast, other antibiotics, such as ciprofloxacin, erythromycin, and clarithromycin, are potent inhibitors of CYP3A4 that result in drug‐drug interactions with drugs metabolized by this isoenzyme (eg, hydrocodone)…”

Section: Discussionsupporting

confidence: 84%

“…The findings of this study are consistent with our understanding of the disposition of delafloxacin in man. Following an intravenous dose of [ 14 C]delafloxacin in healthy subjects in a mass balance study, delafloxacin and its glucuronide metabolites were primarily excreted by the renal route, and only 29% excreted unchanged in the feces . A fraction of a delafloxacin dose is conjugated by the liver into glucuronidated metabolites for excretion by the kidneys, and this process is facilitated through the liver .…”

Section: Discussionmentioning

confidence: 99%

“…Delafloxacin C max values increased proportionally, and area under the plasma concentration‐time curve (AUC 0‐∞ ) showed a more than proportional (6‐fold) increase following single intravenous doses ranging from 300 to 1200 mg in healthy human subjects . The major route of excretion is renal, with 64% of the dose appearing in the urine as parent compound or glucuronide metabolites over a 24‐hour period following a single intravenous dose . The liver is also involved in elimination both through the production of water‐soluble glucuronide conjugates and in the fecal elimination of 29% of an intravenous dose as the unchanged parent compound.…”

mentioning

confidence: 99%

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Clinical Pharmacology of Delafloxacin in Patients With Hepatic Impairment

Hoover¹,

Marbury

Preston

et al. 2016

The Journal of Clinical Pharma

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Delafloxacin is a novel anionic fluoroquinolone with robust activity against Gram‐positive, Gram‐negative, atypical, and anaerobic bacteria, including methicillin‐resistant S aureus. Delafloxacin is currently being studied for the treatment of acute bacterial skin and skin structure infections and community‐acquired pneumonia. This was a phase 1, open‐label pharmacokinetic and safety study of a single intravenous dose of 300 mg delafloxacin in subjects with mild, moderate, and severe hepatic impairment (Child‐Pugh class A, B, and C, respectively) compared with matched healthy controls. The effects of hepatic impairment were assessed by ANOVA of log‐transformed values for AUC0‐∞, Cmax, and systemic clearance, with hepatic group as a fixed effect. Mean AUC0‐∞ and Cmax in each impairment group were not significantly different from those of the pooled healthy subjects (P > 0.05). The 90% confidence interval (CI) of the percentage ratios of least‐squares means of AUC0‐∞ did not indicate significant differences between the impairment groups and pooled healthy controls: Child‐Pugh class A (mild) 114.4 (CI: 95.6, 137.0), Child‐Pugh class B (moderate) 114.8 (CI: 95.9, 137.4), and Child‐Pugh class C (severe) 115.1 (CI: 96.1, 137.8). A single IV infusion of delafloxacin was generally well tolerated in all treatment groups. The exposure and clearance of delafloxacin in subjects with mild, moderate, or severe hepatic impairment did not significantly differ from those of pooled, matched healthy subjects. Based on these pharmacokinetic data, dose adjustment of delafloxacin in the presence of hepatic impairment is not needed.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Clinical Pharmacology of Delafloxacin in Patients With Hepatic Impairment

Hoover¹,

Marbury

Preston

et al. 2016

The Journal of Clinical Pharma

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“…Delafloxacin excretion is approximately two thirds in urine and one third in feces, primarily as unchanged drug. 86 The studies also found that delafloxacin was well tolerated, with the most common adverse effects being gastrointestinal and occurring more frequently at doses of 800 mg or above. Notably, no QTc interval prolongation occurred, which differentiates delafloxacin from other fluoroquinolones.…”

Section: Evidence Summary and Clinical Applicationmentioning

confidence: 93%

Advances in the medical management of skin and soft tissue infections

McClain

Bohan

Stevens

2016

BMJ

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Skin and soft tissue infections are some of the most common infectious disease diagnoses in both inpatient and outpatient settings. With bacterial resistance to antimicrobials growing, decision making on empiric antibiotics is becoming increasingly difficult. Additionally, the most recent guidance from a professional society on the treatment of skin and soft tissue infections was published in 2014 by the Infectious Diseases Society of America and is now two years old. New antimicrobial agents have been developed and approved for the treatment of skin and soft tissue infections since then, and more are in the pipeline. This review summarizes the evidence on treatments that are new or in development and the potential repurposing of old antimicrobials. The clinical utility of these treatments is also discussed.

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“…Additionally, the study confirmed that the main pharmacokinetic parameters were similar to those found in the aforementioned studies. Drug half-life was 2.35 h [17]. The pharmacokinetic parameters of delafloxacin (parent compound) and of other fluoroquinolones used in SSTIs are reported in Table 2.…”

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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Disposition, metabolism and mass balance of delafloxacin in healthy human volunteers following intravenous administration

Cited by 23 publications

References 7 publications

Clinical Pharmacology of Delafloxacin in Patients With Hepatic Impairment

Clinical Pharmacology of Delafloxacin in Patients With Hepatic Impairment

Advances in the medical management of skin and soft tissue infections

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

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