Pharmacokinetics of intravenous and inhaled salbutamol and tobramycin: An exploratory study to investigate the potential of exhaled breath condensate as a matrix for pharmacokinetic analysis

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Abstract

Concentrations of drugs acting in the lungs are difficult to measure, resulting in relatively unknown local pharmacokinetics. The aim of this study is to assess the potential of exhaled breath condensate (EBC) as a matrix for pharmacokinetic analysis of inhaled and intravenous medication. A 4‐way crossover study was conducted in 12 volunteers with tobramycin and salbutamol intravenously and via inhalation. EBC and plasma samples were collected postdose and analysed for drug concentrations. Sample dilution, calculated using urea concentrations, was used to estimate the epithelial lining fluid concentration. Salbutamol and tobramycin were largely undetectable in EBC after intravenous administration and were detectable after inhaled administration in all subjects in 50.8 and 51.5% of EBC samples, respectively. Correction of EBC concentrations for sample dilution did not explain the high variability. This high variability of EBC drug concentrations seems to preclude EBC as a matrix for pharmacokinetic analysis of tobramycin and salbutamol.

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Most cited references 26

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A European Respiratory Society technical standard: exhaled biomarkers in lung disease.

Ildiko Horvath, Peter Barnes, Stelios Loukides … (2017)

Breath tests cover the fraction of nitric oxide in expired gas (FeNO), volatile organic compounds (VOCs), variables in exhaled breath condensate (EBC) and other measurements. For EBC and for FeNO, official recommendations for standardised procedures are more than 10 years old and there is none for exhaled VOCs and particles. The aim of this document is to provide technical standards and recommendations for sample collection and analytic approaches and to highlight future research priorities in the field. For EBC and FeNO, new developments and advances in technology have been evaluated in the current document. This report is not intended to provide clinical guidance on disease diagnosis and management.Clinicians and researchers with expertise in exhaled biomarkers were invited to participate. Published studies regarding methodology of breath tests were selected, discussed and evaluated in a consensus-based manner by the Task Force members.Recommendations for standardisation of sampling, analysing and reporting of data and suggestions for research to cover gaps in the evidence have been created and summarised.Application of breath biomarker measurement in a standardised manner will provide comparable results, thereby facilitating the potential use of these biomarkers in clinical practice.

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Incorporation of concentration data below the limit of quantification in population pharmacokinetic analyses

Ron J. Keizer, Robert Jansen, Hilde Rosing … (2015)

Handling of data below the lower limit of quantification (LLOQ), below the limit of quantification (BLOQ) in population pharmacokinetic (PopPK) analyses is important for reducing bias and imprecision in parameter estimation. We aimed to evaluate whether using the concentration data below the LLOQ has superior performance over several established methods. The performance of this approach (“All data”) was evaluated and compared to other methods: “Discard,” “LLOQ/2,” and “LIKE” (likelihood-based). An analytical and residual error model was constructed on the basis of in-house analytical method validations and analyses from literature, with additional included variability to account for model misspecification. Simulation analyses were performed for various levels of BLOQ, several structural PopPK models, and additional influences. Performance was evaluated by relative root mean squared error (RMSE), and run success for the various BLOQ approaches. Performance was also evaluated for a real PopPK data set. For all PopPK models and levels of censoring, RMSE values were lowest using “All data.” Performance of the “LIKE” method was better than the “LLOQ/2” or “Discard” method. Differences between all methods were small at the lowest level of BLOQ censoring. “LIKE” method resulted in low successful minimization (<50%) and covariance step success (<30%), although estimates were obtained in most runs (∼90%). For the real PK data set (7.4% BLOQ), similar parameter estimates were obtained using all methods. Incorporation of BLOQ concentrations showed superior performance in terms of bias and precision over established BLOQ methods, and shown to be feasible in a real PopPK analysis.

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Intrapulmonary penetration of ceftolozane/tazobactam and piperacillin/tazobactam in healthy adult subjects.

Obiamiwe Umeh, James Huntington, K A Rodvold … (2012)

Appropriate antibiotic exposure at the site of infection is important for clinically effective therapy. This study compared the epithelial lining fluid (ELF) penetration of ceftolozane/tazobactam, which has potent in vitro activity against many Gram-negative pathogens causing nosocomial pneumonia, with that of piperacillin/tazobactam in healthy adult volunteers. In this Phase 1, open-label trial, 51 healthy adult subjects were randomized to receive three doses of either ceftolozane/tazobactam 1.5 g administered every 8 h via a 60 min infusion or piperacillin/tazobactam 4.5 g administered every 6 h via a 30 min infusion. Serial blood samples were obtained for determination of plasma drug concentrations. Bronchoscopy and bronchoalveolar lavage were performed at pre-specified timepoints in five subjects per timepoint in each treatment group to determine the ELF drug concentration. The penetration of individual analytes into the ELF was determined from the ratio of the area under the plasma concentration-time curve in ELF to that in plasma (AUC(ELF)/AUC(plasma)). Plasma and ELF concentrations of ceftolozane, piperacillin and tazobactam increased rapidly, reaching maximal concentrations at the end of the infusion. Mean maximum concentration and AUC from time 0 to the end of the dosing interval (AUC(0-τ)) for ceftolozane in ELF were 21.8 mg/L and 75.1 mg·h/L, respectively. Corresponding values for piperacillin were 58.8 mg/L and 94.5 mg·h/L. The ELF/plasma AUC ratio for ceftolozane was 0.48 compared with 0.26 for piperacillin. This study demonstrated that ceftolozane penetrated well into the ELF following parenteral administration of ceftolozane/tazobactam.

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Author and article information

Contributors

Matthijs D. Kruizinga:

ORCID: https://orcid.org/0000-0002-2054-2187

mkruizinga@chdr.nl

Journal

Journal ID (nlm-ta): Br J Clin Pharmacol

Journal ID (iso-abbrev): Br J Clin Pharmacol

Journal ID (doi): 10.1111/(ISSN)1365-2125

Journal ID (publisher-id): BCP

Title: British Journal of Clinical Pharmacology

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 0306-5251

ISSN (Electronic): 1365-2125

Publication date (Electronic): 03 January 2020

Publication date (Print): January 2020

Publication date PMC-release: 03 January 2020

Volume: 86

Issue: 1 ( doiID: 10.1111/bcp.v86.1 )

Pages: 175-181

Affiliations

[ ¹ ] Centre for Human Drug Research Leiden the Netherlands

[ ² ] Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research Leiden University Leiden the Netherlands

[ ³ ] Ardena Bioanalytical Laboratory BV Assen the Netherlands

Author notes

[*] [* ] Correspondence

Matthijs D. Kruizinga, Centre for Human Drug Research, Zernikedreef 8, 2333CL, Leiden, the Netherlands.

Email: mkruizinga@ 123456chdr.nl

Author information

Matthijs D. Kruizinga https://orcid.org/0000-0002-2054-2187

Willem A.J. Birkhoff https://orcid.org/0000-0001-5832-0646

Michiel J. van Esdonk https://orcid.org/0000-0001-8159-0273

Adam F. Cohen https://orcid.org/0000-0001-7452-6222

Rob G.J.A. Zuiker https://orcid.org/0000-0001-5604-0157

Article

Publisher ID: BCP14156 Other ID: MP-00537-19.R1

DOI: 10.1111/bcp.14156

PMC ID: 6983506

PubMed ID: 31658494

SO-VID: cc93cf3e-e291-4b07-9ec5-8396d2ea0b75

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

History

Date received : 06 July 2019

Date revision received : 11 October 2019

Date accepted : 15 October 2019

Page count

Figures: 1, Tables: 2, Pages: 7, Words: 2434

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cover-date January 2020

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.5 mode:remove_FC converted:27.01.2020

ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: exhaled breath condensate,lung,pharmacokinetics,salbutamol,tobramycin

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ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: exhaled breath condensate, lung, pharmacokinetics, salbutamol, tobramycin

Pharmacokinetics of intravenous and inhaled salbutamol and tobramycin: An exploratory study to investigate the potential of exhaled breath condensate as a matrix for pharmacokinetic analysis

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Dermal Microdialysis in Pharmacokinetics

Most cited references 26

A European Respiratory Society technical standard: exhaled biomarkers in lung disease.

Incorporation of concentration data below the limit of quantification in population pharmacokinetic analyses

Intrapulmonary penetration of ceftolozane/tazobactam and piperacillin/tazobactam in healthy adult subjects.

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