Intrapulmonary pharmacokinetics of cefiderocol, a novel siderophore cephalosporin, in healthy adult subjects

Abstract Background Cefiderocol, a novel siderophore cephalosporin, has shown potent activity against Gram-negative bacteria, including MDR pathogens. Cefiderocol is under clinical investigation for the treatment of serious Gram-negative infections including nosocomial pneumonia. Objectives This study assessed intrapulmonary penetration after a single intravenous dose of cefiderocol (2000 mg infused over 60 min) in healthy adult males. Materials and methods Each subject underwent one bronchoscopy with bronchoalveolar lavage (BAL) to collect BAL fluid (BALF). Fifteen subjects were assigned to one of three collection timepoints (1, 2 or 4 h from start of infusion). Five additional subjects were assigned to a collection timepoint at 6 h, which was added based on concentration data between 1 and 4 h predicting measurable BALF cefiderocol concentrations at 6 h. Results Cefiderocol concentrations in plasma, epithelial lining fluid (ELF) and alveolar macrophages (AMs) were calculated for each subject. The ELF concentration of cefiderocol was 13.8, 6.69, 2.78 and 1.38 mg/L at 1, 2, 4 and 6 h after single intravenous dosing, respectively. Over 6 h, geometric mean concentration ratios ranged from 0.0927 to 0.116 for ELF to total plasma and from 0.00496 to 0.104 for AMs to total plasma. AUC ratios of ELF and AMs to plasma were 0.101 and 0.0177 based on total drug in plasma, respectively, and 0.239 and 0.0419 based on free drug in plasma, respectively. There were no major drug-related adverse events. Conclusions Results of this study indicate that cefiderocol penetrates into ELF, and ELF and plasma concentrations appear to be parallel.

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Comparison of Omadacycline and Tigecycline Pharmacokinetics in the Plasma, Epithelial Lining Fluid, and Alveolar Cells of Healthy Adult Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01135-17 ◽

2017 ◽

Vol 61 (9) ◽

Cited By ~ 39

Author(s):

Mark H. Gotfried ◽

Karolyn Horn ◽

Lynne Garrity-Ryan ◽

Stephen Villano ◽

Evan Tzanis ◽

...

Keyword(s):

Bacterial Infections ◽

Healthy Adult ◽

Plasma Concentrations ◽

Epithelial Lining ◽

Total Plasma ◽

Alveolar Cells ◽

Time Curve ◽

Epithelial Lining Fluid ◽

Time Zero ◽

The Mean

ABSTRACT The steady-state concentrations of omadacycline and tigecycline in the plasma, epithelial lining fluid (ELF), and alveolar cells (AC) of 58 healthy adult subjects were obtained. Subjects were administered either omadacycline at 100 mg intravenously (i.v.) every 12 h for two doses followed by 100 mg i.v. every 24 h for three doses or tigecycline at an initial dose of 100 mg i.v. followed by 50 mg i.v. every 12 h for six doses. A bronchoscopy and bronchoalveolar lavage were performed once in each subject following the start of the fifth dose of omadacycline at 0.5, 1, 2, 4, 8, 12, or 24 h and after the start of the seventh dose of tigecycline at 2, 4, 6, or 12 h. The value of the area under the concentration-time curve (AUC) from time zero to 24 h postdosing (AUC0–24) (based on mean concentrations) in ELF and the ratio of the ELF to total plasma omadacycline concentration based on AUC0–24 values were 17.23 mg · h/liter and 1.47, respectively. The AUC0–24 value in AC was 302.46 mg · h/liter, and the ratio of the AC to total plasma omadacycline concentration was 25.8. In comparison, the values of the AUC from time zero to 12 h postdosing (AUC0–12) based on the mean concentrations of tigecycline in ELF and AC were 3.16 and 38.50 mg · h/liter, respectively. The ratio of the ELF and AC to total plasma concentrations of tigecycline based on AUC0–12 values were 1.71 and 20.8, respectively. The pharmacokinetic advantages of higher and sustained concentrations of omadacycline compared to those of tigecycline in plasma, ELF, and AC suggest that omadacycline is a promising antibacterial agent for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens.

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Plasma and Intrapulmonary Concentrations of Cefepime and Zidebactam following Intravenous Administration of WCK 5222 to Healthy Adult Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00682-18 ◽

2018 ◽

Vol 62 (8) ◽

Cited By ~ 12

Author(s):

Keith A. Rodvold ◽

Mark H. Gotfried ◽

Rakesh Chugh ◽

Mugdha Gupta ◽

Anasuya Patel ◽

...

Keyword(s):

Bacterial Infections ◽

Healthy Adult ◽

Plasma Concentrations ◽

Sampling Time ◽

Pharmacokinetic Parameters ◽

The Novel ◽

Total Plasma ◽

Dosing Regimen ◽

Time Curve ◽

Epithelial Lining Fluid

ABSTRACTWCK 5222 is a combination of cefepime and the novel β-lactam enhancer zidebactam being developed for the treatment of serious Gram-negative bacterial infections. The objective of this study was to compare plasma (total), epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of cefepime and zidebactam in healthy adult subjects. The WCK 5222 dosing regimen was 2 g cefepime/1 g zidebactam administered as a 1-h intravenous infusion every 8 h for a total of 7 doses. Subjects were assigned to one bronchoalveolar lavage (BAL) sampling time at 0.5, 1.25, 3, 6, 8, or 10 h after the seventh dose. Noncompartmental pharmacokinetic parameters were determined from serial plasma concentrations collected over 8-hour and 10-hour intervals following the first and seventh doses, respectively. Penetration ratios were calculated from the area under the plasma concentration-time curve from 0 to 8 h (AUC0–8) for plasma, ELF, and AM using mean and median concentrations at each BAL sampling time. The plasma maximum concentration of drug (Cmax) and AUC values of cefepime and zidebactam increased by 8% to 9% after the seventh versus the first dose of WCK 5222. The respective AUC0–8values based on mean concentrations of cefepime and zidebactam in ELF were 127.9 and 52.0 mg · h/liter, and 87.9 and 13.2 mg · h/liter in AM. The ELF to total plasma penetration ratios of cefepime and zidebactam based on mean AUC0–8values were 0.39 and 0.38, respectively. The AM to total plasma ratios were 0.27 and 0.10, respectively. The observed plasma, ELF, and AM concentrations of cefepime and zidebactam support studies of WCK 5222 for treatment of pneumonia caused by susceptible pathogens.

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Comparison of Plasma, Epithelial Lining Fluid, and Alveolar Macrophage Concentrations of Solithromycin (CEM-101) in Healthy Adult Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00766-12 ◽

2012 ◽

Vol 56 (10) ◽

pp. 5076-5081 ◽

Cited By ~ 39

Author(s):

Keith A. Rodvold ◽

Mark H. Gotfried ◽

J. Gordon Still ◽

Kay Clark ◽

Prabhavathi Fernandes

Keyword(s):

Steady State ◽

High Performance ◽

Healthy Adult ◽

Plasma Concentrations ◽

Epithelial Lining ◽

Time Curve ◽

Epithelial Lining Fluid ◽

Once Daily ◽

Drug Concentrations ◽

The Mean

ABSTRACTThe steady-state concentrations of solithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from intrapulmonary samples during bronchoscopy and bronchoalveolar lavage (BAL) in 30 healthy adult subjects. Subjects received oral solithromycin at 400 mg once daily for five consecutive days. Bronchoscopy and BAL were carried out once in each subject at either 3, 6, 9, 12, or 24 h after the last administered dose of solithromycin. Drug concentrations in plasma, ELF, and AM were assayed by a high-performance liquid chromatography-tandem mass spectrometry method. Solithromycin was concentrated extensively in ELF (range of mean [± standard deviation] concentrations, 1.02 ± 0.83 to 7.58 ± 6.69 mg/liter) and AM (25.9 ± 20.3 to 101.7 ± 52.6 mg/liter) in comparison with simultaneous plasma concentrations (0.086 ± 0.070 to 0.730 ± 0.692 mg/liter). The values for the area under the concentration-time curve from 0 to 24 h (AUC0–24values) based on mean and median ELF concentrations were 80.3 and 63.2 mg · h/liter, respectively. The ratio of ELF to plasma concentrations based on the mean and median AUC0–24values were 10.3 and 10.0, respectively. The AUC0–24values based on mean and median concentrations in AM were 1,498 and 1,282 mg · h/L, respectively. The ratio of AM to plasma concentrations based on the mean and median AUC0–24values were 193 and 202, respectively. Once-daily oral dosing of solithromycin at 400 mg produced steady-state concentrations that were significantly (P< 0.05) higher in ELF (2.4 to 28.6 times) and AM (44 to 515 times) than simultaneous plasma concentrations throughout the 24-h period after 5 days of solithromycin administration.

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Lack of Effect of Efavirenz on the Pharmacokinetics of Tipranavir-Ritonavir in Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00462-09 ◽

2009 ◽

Vol 53 (11) ◽

pp. 4840-4844 ◽

Cited By ~ 5

Author(s):

C. J. L. la Porte ◽

J. P. Sabo ◽

L. Béïque ◽

D. W. Cameron

Keyword(s):

Steady State ◽

Multiple Dose ◽

Healthy Adult ◽

Geometric Mean ◽

Plasma Concentrations ◽

Open Label ◽

Multiple Dose Study ◽

Chromatography Tandem Mass Spectrometry ◽

Liquid Chromatography Tandem Mass ◽

Dose Study

ABSTRACT Previously it has been shown that tipranavir-ritonavir (TPV/r) does not affect efavirenz (EFV) plasma concentrations. This study investigates the effect of steady-state EFV on steady-state TPV/r pharmacokinetics. This was a single-center, open-label, multiple-dose study of healthy adult female and male volunteers. TPV/r 500/200 mg twice a day (BID) was given with food for 24 days. After dosing with TPV/r for 10 days, EFV 600 mg once a day was added to the regimen. Intensive pharmacokinetic (PK) sampling was done on days 10 and 24. Validated bioanalytical high-pressure liquid chromatography-tandem mass spectrometry methods were used to determine plasma tipranavir (TPV), ritonavir (RTV), and EFV concentrations. Thirty-four subjects were entered into the study, and 16 subjects completed it. The geometric mean ratios (90% confidence intervals) for TPV and RTV area under the curves, C maxs, and C mins comparing TPV/r alone and in combination with EFV were 0.97 (0.87 to 1.09), 0.92 (0.81 to 1.03), and 1.19 (0.93 to 1.54) for TPV and 1.03 (0.78 to 1.38), 0.92 (0.65 to 1.30), and 1.04 (0.72 to 1.48) for RTV. Frequently observed adverse events were diarrhea, headache, dizziness, abnormal dreams, and rash. EFV had no effect on the steady-state PK of TPV or RTV, with the exception of a 19% increase in the TPV C min, which is not clinically relevant. TPV/r can be safely coadministered with EFV and without the need for a dose adjustment.

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Comparison of Plasma and Intrapulmonary Concentrations of Nafithromycin (WCK 4873) in Healthy Adult Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01096-17 ◽

2017 ◽

Vol 61 (9) ◽

Cited By ~ 7

Author(s):

Keith A. Rodvold ◽

Mark H. Gotfried ◽

Rakesh Chugh ◽

Mugdha Gupta ◽

H. David Friedland ◽

...

Keyword(s):

Healthy Adult ◽

Plasma Concentrations ◽

Maximum Plasma ◽

Total Plasma ◽

Time Curve ◽

The Third ◽

Elimination Half ◽

The Mean ◽

Repeated Dosing ◽

Tract Infections

ABSTRACT The nafithromycin concentrations in the plasma, epithelial lining fluid (ELF), and alveolar macrophages (AM) of 37 healthy adult subjects were measured following repeated dosing of oral nafithromycin at 800 mg once daily for 3 days. The values of noncompartmental pharmacokinetic (PK) parameters were determined from serial plasma samples collected over a 24-h interval following the first and third oral doses. Each subject underwent one standardized bronchoscopy with bronchoalveolar lavage (BAL) at 3, 6, 9, 12, 24, or 48 h after the third dose of nafithromycin. The mean ± standard deviation values of the plasma PK parameters after the first and third doses included maximum plasma concentrations (C max) of 1.02 ± 0.31 μg/ml and 1.39 ± 0.36 μg/ml, respectively; times to C max of 3.97 ± 1.30 h and 3.69 ± 1.28 h, respectively; clearances of 67.3 ± 21.3 liters/h and 52.4 ± 18.5 liters/h, respectively, and elimination half-lives of 7.7 ± 1.1 h and 9.1 ± 1.7 h, respectively. The values of the area under the plasma concentration-time curve (AUC) from time zero to 24 h postdosing (AUC0–24) for nafithromycin based on the mean or median total plasma concentrations at BAL fluid sampling times were 16.2 μg · h/ml. For ELF, the respective AUC0–24 values based on the mean and median concentrations were 224.1 and 176.3 μg · h/ml, whereas for AM, the respective AUC0–24 values were 8,538 and 5,894 μg · h/ml. Penetration ratios based on ELF and total plasma AUC0–24 values based on the mean and median concentrations were 13.8 and 10.9, respectively, whereas the ratios of the AM to total plasma concentrations based on the mean and median concentrations were 527 and 364, respectively. The sustained ELF and AM concentrations for 48 h after the third dose suggest that nafithromycin has the potential to be a useful agent for the treatment of lower respiratory tract infections. (This study has been registered at ClinicalTrials.gov under registration no. NCT02453529.)

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Dasatinib Can Be Administered Orally with or without a Meal.

Blood ◽

10.1182/blood.v110.11.4569.4569 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4569-4569 ◽

Cited By ~ 2

Author(s):

Sanjeev Kaul ◽

Chiyuan Wu ◽

Shelley Mayfield ◽

James Manning ◽

Anne Blackwood-Chirchir

Keyword(s):

Adverse Events ◽

Healthy Adult ◽

Geometric Mean ◽

Plasma Concentrations ◽

Mass Spectrometric Method ◽

High Fat ◽

Low Fat ◽

Fasted State ◽

Tandem Mass Spectrometric ◽

Fat Meal

Abstract Background: Food can change the bioavailability of a drug, which can have clinically significant consequences. This study was conducted to investigate the effect of food on the oral bioavailability of dasatinib (SPRYCEL®) in healthy adult subjects. Methods: Fifty-four healthy adult subjects received a single dose of dasatinib 100 mg dose, as 2 x 50 mg film-coated tablets after an overnight fast and within 10 minutes after the ingestion of a low-fat meal (315 kcal [20% fat, 68% carbohydrates, and 12% protein]) and a high-fat meal (985 kcal [52% fat, 34% carbohydrates, and 14% protein]) in a randomly assigned sequence. Individual treatments were separated by at least a 7-day washout period. Serial blood samples were collected for 24 hours after each treatment to determine dasatinib plasma concentrations using a validated liquid chromatography/tandem mass spectrometric method. Dasatinib pharmacokinetic (PK) parameters were determined using a non-compartmental method. Safety was monitored throughout the study. Results: Of the 54 healthy adult subjects (85% male, 61% Caucasian, mean age 32 y, and weight 80 kg), 48 completed the study. There were no serious adverse events. Adverse events and laboratory abnormalities were, in general, typical of those seen with dasatinib administration. PK results are summarized in the table below. Conclusions: Compared to the fasted state, a low-fat meal decreased Cmax and AUC of dasatinib by 21%; a high-fat meal decreased Cmax by 24% and increased AUC by 14%. These results are not expected to be of clinical relevance and, therefore, dasatinib may be taken without regard to meals. The drug was generally safe and well-tolerated when administered in the fed or fasted state. Statistical Analysis of PK Parameters for Dasatinib Treatment PK Parameter Geometric Mean Ratios (95% Confidence Intervals) Fed versus Fasted Low-Fat Meal Cmax 1.216 (1.047, 1.413) AUC 1.212 (1.100, 1.336) High-Fat Meal Cmax 0.758 (0.651, 0.882) AUC 1.140 (1.034, 1.257)

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1302. Cefiderocol Population Pharmacokinetics and Probability of Target Attainment in Plasma and Epithelial Lining Fluid in Patients with Pneumonia, Bloodstream Infection/Sepsis, or Complicated Urinary Tract Infections

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1485 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S665-S665

Author(s):

Takayuki Katsube ◽

Nao Kawaguchi ◽

Roger Echols ◽

Toshihiro Wajima ◽

David P Nicolau

Keyword(s):

Renal Function ◽

Urinary Tract ◽

Healthy Subjects ◽

Epithelial Lining ◽

Infection Site ◽

Target Attainment ◽

Research Support ◽

Concentration Data ◽

Epithelial Lining Fluid ◽

Gram Negative

Abstract Background Cefiderocol (CFDC) is a novel siderophore cephalosporin with activity against a broad range of Gram-negative bacteria. The aim of this study was to perform population pharmacokinetic (PopPK) analysis and evaluate probability of target attainment (PTA) in plasma and epithelial lining fluid (ELF) based on a modeling and simulation approach. Methods PopPK analysis in plasma was conducted using 3427 concentration data from 425 patients with pneumonia, bloodstream infection/sepsis (BSI/sepsis), complicated urinary tract infection (cUTI), or acute uncomplicated pyelonephritis in 3 Phase 2 or 3 studies (NCT03032380, NCT02714595, and NCT02321800), and 91 subjects without any infection in Phase 1 studies. In addition, intrapulmonary modeling was conducted using ELF concentration data from 7 pneumonia patients (NCT03862040) and 20 healthy subjects. Monte-Carlo simulations were performed by generating 1000 virtual patients for each infection site (pneumonia, BSI/sepsis, or cUTI) to predict PTA for 75% of time for which free drug concentration in plasma or ELF (only pneumonia patients) exceeds the minimum inhibitory concentration (MIC; 0.25–16 µg/mL) over dosing interval following CFDC 2 g q8h infused over 3 hours with dose adjustment based on renal function, including augmented renal clearance. Results The developed PopPK model described the plasma and ELF CFDC concentrations. Creatinine clearance, body weight, infection site, and albumin concentration were statistically significant covariates on CFDC PK in plasma. There were no clinically significant differences in CFDC plasma exposure based on infection site or with/without ventilation. The penetration ratio of ELF to free plasma in pneumonia patients (0.340) was 1.3-fold higher than that in healthy subjects (0.263). As shown in the table below, plasma PTA was >90% against MICs ≤4 μg/mL, regardless of infection site and renal function. ELF PTA in pneumonia patients was >90% against MICs ≤2 μg/mL and >85% against MICs ≤4 μg/mL, regardless of renal function. Table. Probability of Target Attainment for 75% fT>MIC or 75% fT>MIC,ELF Conclusion The recommended dosing regimen (2 g, q8h, 3-hr infusion) adjusted by renal function provided adequate exposure to CFDC in patients with infections caused by Gram-negative pathogens, irrespective of infection site and renal function. Disclosures Takayuki Katsube, PhD, Shionogi & Co., Ltd. (Employee) Nao Kawaguchi, BPharm, Shionogi & Co., Ltd. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant) Toshihiro Wajima, PhD, Shionogi & Co., Ltd. (Employee) David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)

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Plasma and Intrapulmonary Concentrations of ETX2514 and Sulbactam following Intravenous Administration of ETX2514SUL to Healthy Adult Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01089-18 ◽

2018 ◽

Vol 62 (11) ◽

Cited By ~ 11

Author(s):

Keith A. Rodvold ◽

Mark H. Gotfried ◽

Robin D. Isaacs ◽

John P. O'Donnell ◽

Emily Stone

Keyword(s):

Healthy Adult ◽

Plasma Concentrations ◽

Multidrug Resistant ◽

Time Curve ◽

Epithelial Lining Fluid ◽

Content Type ◽

Liquid Chromatography Tandem Mass ◽

Repeated Dosing ◽

Sampling Times

ABSTRACT ETX2514 is a novel β-lactamase inhibitor that broadly inhibits Ambler class A, C, and D β-lactamases. ETX2514 combined with sulbactam (SUL) in vitro restores sulbactam activity against Acinetobacter baumannii. ETX2514-sulbactam (ETX2514SUL) is under development for the treatment of A. baumannii infections. The objective of this study was to determine and compare plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations following intravenous (i.v.) ETX2514 and sulbactam. Plasma, ELF, and AM concentrations of ETX2514 and sulbactam were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 30 healthy adult subjects following repeated dosing (ETX2514 [1 g] and sulbactam [1 g] every 6 h [q6h], as a 3-h i.v. infusion, for a total of 3 doses). A bronchoalveolar lavage (BAL) was performed once in each subject at either 1, 2.5, 3.25, 4, or 6 h after the start of the last infusion. Penetration ratios were calculated from area under the concentration-time curve from 0 to 6 h (AUC0–6) values for total plasma and ELF using mean and median concentrations at the BAL fluid sampling times. Respective ELF AUC0–6 values, based on mean and median concentrations, were 40.1 and 39.4 mg · h/liter for ETX2514 and 34.7 and 34.5 mg · h/liter for sulbactam. Respective penetration ratios of ELF to total/unbound plasma concentrations, based on mean and median AUC0–6 values, of ETX2514 were 0.37/0.41 and 0.36/0.40, whereas these same ratio values were 0.50/0.81 and 0.50/0.80 for sulbactam. ETX2514 and sulbactam concentrations in AM were measurable and fairly constant throughout the dosing interval (median values of 1.31 and 1.01 mg/liter, respectively). These data support further study of ETX2514SUL for the treatment of pneumonia caused by multidrug-resistant A. baumannii. (This study has been registered at ClinicalTrials.gov under identifier NCT03303924.)

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