Microdosing as a Potential Tool to Enhance Clinical Development of Novel Antibiotics: A Tissue and Plasma PK Feasibility Study with Ciprofloxacin
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Published on: August 30, 2018
Zoe Oesterreicher1,2, Sabine Eberl1, Beatrix Wulkersdorfer1
1Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
Background And Objective:
In microdose studies, drug pharmacokinetics is measured in humans after administration of subtherapeutic doses. While previous microdose studies focused primarily on plasma pharmacokinetics, we set out to evaluate the feasibility of microdosing for a pharmacokinetic assessment in subcutaneous tissue and epithelial lining fluid.
Methods:
Healthy subjects received a single intravenous bolus injection of a microdose of [14C]ciprofloxacin (1.1 µg, 7 kBq) with (cohort A, n = 9) or without (cohort B, n = 9) a prior intravenous infusion of a therapeutic dose of unlabeled ciprofloxacin (400 mg). Microdialysis and bronchoalveolar lavage were applied for determination of subcutaneous and intrapulmonary drug concentrations. Microdose [14C]ciprofloxacin was quantified by accelerator mass spectrometry and therapeutic-dose ciprofloxacin by liquid chromatography-tandem mass spectrometry.
Results:
The pharmacokinetics of therapeutic-dose ciprofloxacin (cohort A) in plasma, subcutaneous tissue, and epithelial lining fluid was in accordance with previous data. In plasma and subcutaneous tissue, the dose-adjusted area under the concentration-time curve of microdose ciprofloxacin was similar in cohorts A and B and within an 0.8-fold to 1.1-fold range of the area under the concentration-time curve of therapeutic-dose ciprofloxacin. Penetration of microdose ciprofloxacin into subcutaneous tissue was similar in cohorts A and B and comparable to that of therapeutic-dose ciprofloxacin with subcutaneous tissue-to-plasma area under the concentration-time curve ratios of 0.44, 0.44, and 0.38, respectively. Penetration of microdose ciprofloxacin into epithelial lining fluid was highly variable and failed to predict the epithelial lining fluid penetration of therapeutic-dose ciprofloxacin.
Conclusions:
Our study confirms the feasibility of microdosing for pharmacokinetic measurements in plasma and subcutaneous tissue. Microdosing combined with microdialysis is a potentially useful tool in clinical antimicrobial drug development, but its applicability for the assessment of pulmonary pharmacokinetics with bronchoalveolar lavage requires further studies.
Clinical Trial Registration:
ClinicalTrials.gov NCT03177720 (registered 6 June, 2017).
Insights
Microdosing drug pharmacokinetics is feasible in human plasma and subcutaneous tissue, but not yet reliable for lung tissue. This method shows promise for antimicrobial drug development.
Area of Science:
- Pharmacology
- Drug Development
- Clinical Pharmacology
Background:
- Microdose studies traditionally focus on plasma pharmacokinetics.
- This study explores microdosing for subcutaneous tissue and epithelial lining fluid pharmacokinetics.
Purpose of the Study:
- To evaluate the feasibility of microdosing for pharmacokinetic assessment in subcutaneous tissue and epithelial lining fluid.
- To compare microdose pharmacokinetics with therapeutic-dose pharmacokinetics.
Main Methods:
- Healthy subjects received microdose [14C]ciprofloxacin with or without a prior therapeutic dose.
- Microdialysis and bronchoalveolar lavage were used to determine drug concentrations.
- Accelerator mass spectrometry quantified microdose ciprofloxacin.
Main Results:
- Microdosing accurately predicted therapeutic-dose pharmacokinetics in plasma and subcutaneous tissue.
- Subcutaneous tissue penetration of microdose ciprofloxacin was comparable to therapeutic doses.
- Epithelial lining fluid penetration of microdose ciprofloxacin was highly variable and did not predict therapeutic levels.
Conclusions:
- Microdosing is feasible for pharmacokinetic measurements in plasma and subcutaneous tissue.
- Microdosing with microdialysis is a promising tool for antimicrobial drug development.
- Further studies are needed to assess microdosing for pulmonary pharmacokinetics.
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