Evaluation of Innovative Tools in Development of Antibiotics

Determination of Single-dose Intrapulmonary Pharmacokinetics of Ciprofloxacin and Imipenem in Healthy Subjects and Intubated Patients Suffering From Pneumonia Using Bronchoalveolar Lavage

The investigators will determine the difference of pharmacokinetics of ciprofloxacin and imipenem between healthy volunteers and intensive care patients suffering from pneumonia in plasma and at the target site - lung - using bronchoalveolar lavage. As additional aspect the feasibility of combining microdosing of C14 ciprofloxacin with microdialysis, saliva sampling and bronchoalveolar lavage is studied by comparing pharmacokinetics of microdose and macrodose.

Study Overview

• Status: Completed
• Conditions: Pneumonia
• Intervention / Treatment: Drug: Ciprofloxacin; Drug: Imipenem

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Medical University of Vienna

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy male subjects aged 18 to 55 years
• Good state of health (mentally and physically)
• Body mass index within a range of 18 to 28kg/m2 inclusive.
• Non-Smoker
• A signed and dated written informed consent form.
• The subject is able to understand and willing to comply with protocol requirements and timetables, instructions and protocol-stated restrictions.
• Negative serology (human immunodeficiency virus, hepatitis B-AG and C-AB) at screening.
• Vital signs should be within the following ranges:
• Oral or tympanic temperature between 35 and 37.5°C.
• Systolic blood pressure, 90-140 mmHg.
• Diastolic blood pressure, 50-90 mmHg.
• Pulse rate, 50-90 bpm.

Exclusion Criteria:

• Any acute or chronic illness or clinically relevant (Investigator's judgement) abnormality identified on the screening medical assessment, laboratory tests or ECG, unless in the opinion of the Investigator it will not interfere with the study procedures, affect the outcome of the study or compromise the safety of the subject.
• All subjects with known seizure disorder, with the exception of a febrile seizure in childhood
• Use of prescription or non-prescription drugs within 7 days or 10 times the elimination half-life (whichever is longer) prior to the first dose of study medication.
• Any intake of grapefruit juice within 1 week prior to the first dose.
• Allergies (except for mild forms of hay fever), a history of hypersensitivity reactions including psychological or neurological symptoms or signs, or anaphylactic shock following administration of any medicine.
• Allergy to or any contraindication against the active or inactive ingredients in the study medication (ciprofloxacin, imipenem, cilastatin, propofol, midazolam, remifentanil, xylocain, and sevoflurane) and radioactive labelling with 14C.
• Smoker
• Alcohol or drug abuse
• Participation in a trial with any drug within 30 days or five half-lives (whichever is longer) before the start of the study.
• Donation of blood within a period of 4 weeks prior to dosing.
• Creatinine clearance ≤70mL/min/1.73m3
• Any other reason that the Investigator considers to make the subject unsuitable to participate.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ciprofloxacin; Half of patients and healthy volunteers are receiving ciprofloxacin, the other half imipenem.	Drug: Ciprofloxacin; Ciprofloxacin 400mg will be administered as single dose infusion over 60 minutes, imipenem/cilastatin 1000mg as single intravenous dose applicated over 60 minutes.
Active Comparator: Imipenem; Half of patients and healthy volunteers are receiving ciprofloxacin, the other half imipenem.	Drug: Imipenem; Ciprofloxacin 400mg will be administered as single dose infusion over 60 minutes, imipenem/cilastatin 1000mg as single intravenous dose applicated over 60 minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax (peak concentration in plasma and epithelial lining fluid) of imipenem and ciprofloxacin	Comparison of Cmax of ciprofloxacin and imipenem in plasma and epithelial lining fluid, alveolar macrophages and saliva (only healthy subjects) in healthy subjects and patients with bacterial pneumonia.	Plasma over 10 hours and BAL (bronchoalveolar lavage) Sampling at different time points in these 10 hours.
AUC (area under the concentration curve in plasma and epithelial lining fluid) of imipenem and ciprofloxacin.	Comparison of AUC of ciprofloxacin and imipenem in plasma and epithelial lining fluid, alveolar macrophages and saliva (only healthy subjects) in healthy subjects and patients with bacterial pneumonia.	Plasma over 10 hours and BAL Sampling at different time points in these 10 hours.
Tmax (time of peak concentration in plasma and epithelial lining fluid) of imipenem and ciprofloxacin.	Comparison of AUC of ciprofloxacin and imipenem in plasma and epithelial lining fluid, alveolar macrophages and saliva (only healthy subjects) in healthy subjects and patients with bacterial pneumonia.	Plasma over 10 hours and BAL Sampling at different time points in these 10 hours.
Cmax (peak concentration in plasma, epithelial lining fluid and microdialysate) of C14 ciprofloxacin (microdose)	Comparison of pharmacokinetics of microdoses and macrodoses in lung, subcutaneous tissue (microdialysis) and plasma in healthy volunteers.	Plasma sampling over 10 hours and microdialysate sampling.
AUC (area under the curve in plasma, epithelial lining fluid and microdialysate) of C14 ciprofloxacin (carbon-14 radiolabelled compound, microdose)	Comparison of pharmacokinetics of microdoses and macrodoses in lung, subcutaneous tissue (microdialysis) and plasma in healthy volunteers.	Plasma sampling over 10 hours and microdialysate sampling.
Tmax (time of peak concentration in plasma, epithelial lining fluid and microdialysate) of C14 ciprofloxacin (microdose)	Comparison of pharmacokinetics of microdoses and macrodoses in lung, subcutaneous tissue (microdialysis) and plasma in healthy volunteers.	Plasma sampling over 10 hours and microdialysate sampling.
Cmax (peak concentration in microdialysate) of ciprofloxacin (macrodose)	In healthy volunteers only for comparison of Cmax of C14 ciprofloxacin and Cmax of ciprofloxacin as macrodose.	Microdialysate sampling (Baseline sampling before study drug administration - sampling over 3 hours - retrodialysis)
AUC (area under the concentration curve in microdialysate) of ciprofloxacin (macrodose)	In healthy volunteers only for comparison of Cmax of C14 ciprofloxacin and Cmax of ciprofloxacin as macrodose.	Microdialysate sampling (Baseline sampling before study drug administration - sampling over 3 hours - retrodialysis)
Tmax (time of peak concentration in microdialysate) of ciprofloxacin (macrodose)	In healthy volunteers only for comparison of Cmax of C14 ciprofloxacin and Cmax of ciprofloxacin as macrodose.	Microdialysate sampling (Baseline sampling before study drug administration - sampling over 3 hours - retrodialysis)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment Emergent Adverse Events	Incidence of Treatment Emergent Adverse Events (Study drugs: ciprofloxacin, 14C labelled ciprofloxacin and imipenem)	Screening visit and final examination are performed up to 7 days before/after the actual study day and safety and tolerability assessed.

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Investigators: Principal Investigator: Markus Zeitlinger, MD, Medical University of Vienna

Publications and helpful links

General Publications

• Oesterreicher Z, Eberl S, Wulkersdorfer B, Matzneller P, Eder C, van Duijn E, Vaes WHJ, Reiter B, Stimpfl T, Jager W, Nussbaumer-Proell A, Marhofer D, Marhofer P, Langer O, Zeitlinger M. Microdosing as a Potential Tool to Enhance Clinical Development of Novel Antibiotics: A Tissue and Plasma PK Feasibility Study with Ciprofloxacin. Clin Pharmacokinet. 2022 May;61(5):697-707. doi: 10.1007/s40262-021-01091-1. Epub 2022 Jan 7.

Study record dates

Study Major Dates

• Study Start (Actual): May 29, 2016
• Primary Completion (Actual): July 31, 2021
• Study Completion (Actual): July 31, 2021

Study Registration Dates

• First Submitted: May 30, 2017
• First Submitted That Met QC Criteria: June 2, 2017
• First Posted (Actual): June 6, 2017

Study Record Updates

• Last Update Posted (Actual): September 1, 2021
• Last Update Submitted That Met QC Criteria: August 31, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Pneumonia; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Ciprofloxacin; Imipenem
• Other Study ID Numbers: ELF Cipro

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No