Dataset Information

Intrapulmonary Pharmacokinetics of Levonadifloxacin following Oral Administration of Alalevonadifloxacin to Healthy Adult Subjects.

ABSTRACT: Alalevonadifloxacin (WCK 2349) is a novel l-alanine ester prodrug of levonadifloxacin that is being developed as an oral fluoroquinolone antibiotic. The primary objective of this study was to determine and compare plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of levonadifloxacin following oral administration of alalevonadifloxacin to healthy adult subjects. Levonadifloxacin concentrations in plasma, ELF, and AM samples from 30 healthy subjects were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) following oral dosing of alalevonadifloxacin (1,000 mg twice daily for 5 days). Six subjects were assigned to each bronchoalveolar lavage (BAL) fluid sampling time, i.e., 2, 4, 6, 8, or 12 h after the ninth oral dose. Noncompartmental pharmacokinetic (PK) parameters were determined from serial total plasma concentrations collected over a 12-h interval following the first and ninth oral doses. Penetration ratios were calculated from the areas under the concentration-time curves from 0 to 12 h (AUC0-12) for plasma, ELF, and AM by using mean (and median) concentrations at each BAL sampling time. Unbound plasma concentrations (?85% plasma protein binding) were used to determine site-to-plasma penetration ratios. Plasma PK parameter values for levonadifloxacin were similar after the first and ninth doses. The respective AUC0-12 values based on mean ELF and AM concentrations were 172.6 and 35.3 mg · h/liter, respectively. The penetration ratios for ELF and AM levonadifloxacin concentrations to unbound plasma levonadifloxacin concentrations were 7.66 and 1.58, respectively. Similar penetration ratios were observed with median concentrations. The observed plasma, ELF, and AM concentrations of levonadifloxacin support further studies of alalevonadifloxacin for treatment of lower respiratory tract bacterial infections caused by susceptible pathogens. (This study has been registered at ClinicalTrials.gov under identifier NCT02253342.).

SUBMITTER: Rodvold KA

PROVIDER: S-EPMC5826115 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Intrapulmonary Pharmacokinetics of Levonadifloxacin following Oral Administration of Alalevonadifloxacin to Healthy Adult Subjects.

Rodvold Keith A KA Gotfried Mark H MH Chugh Rakesh R Gupta Mugdha M Yeole Ravindra R Patel Anasuya A Bhatia Ashima A

Antimicrobial agents and chemotherapy 20180223 3

Alalevonadifloxacin (WCK 2349) is a novel l-alanine ester prodrug of levonadifloxacin that is being developed as an oral fluoroquinolone antibiotic. The primary objective of this study was to determine and compare plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of levonadifloxacin following oral administration of alalevonadifloxacin to healthy adult subjects. Levonadifloxacin concentrations in plasma, ELF, and AM samples from 30 healthy subjects were measured b ...[more]

PMID: 29263070

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Project description:Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral carbapenem prodrug being developed for the treatment of serious bacterial infections. The active moiety, tebipenem, has broad-spectrum activity against common Enterobacterales pathogens, including extended-spectrum-β-lactamase (ESBL)-producing multidrug-resistant strains. This study evaluated the intrapulmonary pharmacokinetics (PK) and epithelial lining fluid (ELF) and alveolar macrophage (AM) concentrations of tebipenem relative to plasma levels in nonsmoking, healthy adult subjects. Thirty subjects received oral TBP-PI-HBr at 600 mg every 8 h for five doses. Serial blood samples were collected following the last dose. Each subject underwent one standardized bronchoscopy with bronchoalveolar lavage (BAL) 1, 2, 4, 6, or 8 h after the fifth dose of TBP-PI-HBr. The tebipenem area under the concentration-time curve for the 8-h dosing interval (AUC0-8) values in plasma, ELF, and AMs were calculated using the mean concentration at each BAL sampling time. Ratios of AUC0-8 values for total ELF and AMs to those for unbound plasma were determined, using a plasma protein binding value of 42%. Mean values ± standard deviations (SD) of tebipenem maximum (Cmax) and minimum (Cmin) total plasma concentrations were 11.37 ± 3.87 mg/L and 0.043 ± 0.039 mg/L, respectively. Peak tebipenem concentrations in plasma, ELF, and AMs occurred at 1 h and then decreased over 8 h. Ratios of tebipenem AUC0-8 values for ELF and AMs to those for unbound plasma were 0.191 and 0.047, respectively. Four (13.3%) subjects experienced adverse events (diarrhea, fatigue, papule, and coronavirus disease 2019 [COVID-19]); all resolved, and none were severe or serious. Tebipenem is distributed into the lungs of healthy adults, which supports the further evaluation of TBP-PI-HBr for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens. (This study has been registered at ClinicalTrials.gov under identifier NCT04710407.).

Dataset Information

Intrapulmonary Pharmacokinetics of Levonadifloxacin following Oral Administration of Alalevonadifloxacin to Healthy Adult Subjects.

Publications

Intrapulmonary Pharmacokinetics of Levonadifloxacin following Oral Administration of Alalevonadifloxacin to Healthy Adult Subjects.

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