Microdosing as a Potential Tool to Enhance Clinical Development of Novel Antibiotics: A Tissue and Plasma PK Feasibility Study with Ciprofloxacin
Z. Oesterreicher, Sabine Eberl, B. Wulkersdorfer, P. Matzneller, C. Eder, E. van Duijn, W. Vaes, B. Reiter, Thomas Stimpfl, W. Jäger, A. Nussbaumer-Proell, D. Marhofer, P. Marhofer, Oliver Langer, Markus Zeitlinger
Clinical Pharmacokinetics January 7, 2022 DOI: 10.1007/s40262-021-01091-1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort Peer reviewed |
|---|---|
| Sample size | 18 |
| Population | Healthy subjects |
| Dose | 1.1 µg microdose; 400 mg therapeutic dose |
| Duration | Single administration |
| Measures | Area under the concentration-time curve (AUC), subcutaneous tissue-to-plasma AUC ratio, epithelial lining fluid penetration |
| Topics | Microdosing |
| Registration | NCT03177720 |
| Key findings | Microdose ciprofloxacin pharmacokinetics in plasma and subcutaneous tissue predicts therapeutic-dose pharmacokinetics, but not in epithelial lining fluid. |
Abstract
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 [ 14 C]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 [ 14 C]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).