Clinical trial NCT03177720: Evaluation of Innovative Tools in Development of Antibiotics
Official title: Determination of Single-dose Intrapulmonary Pharmacokinetics of Ciprofloxacin and Imipenem in Healthy Subjects and Intubated Patients Suffering From Pneumonia Using Bronchoalveolar Lavage
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pneumonia
Lead sponsor: Medical University of Vienna
Sponsor class: OTHER
First posted: 2017-06-06
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 24 patients and 18 healthy volunteers are included. 12 patients and 9 volunteers are receiving imipenem as study drug, the other 12 patients and 9 volunteers receive ciprofloxacin.
Primary purpose: OTHER

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Cmax (peak concentration in plasma and epithelial lining fluid) of imipenem and ciprofloxacin
timeFrame: Plasma over 10 hours and BAL (bronchoalveolar lavage) Sampling at different time points in these 10 hours.
measure: AUC (area under the concentration curve in plasma and epithelial lining fluid) of imipenem and ciprofloxacin.
timeFrame: Plasma over 10 hours and BAL Sampling at different time points in these 10 hours.
measure: Tmax (time of peak concentration in plasma and epithelial lining fluid) of imipenem and ciprofloxacin.
timeFrame: Plasma over 10 hours and BAL Sampling at different time points in these 10 hours.
measure: Cmax (peak concentration in plasma, epithelial lining fluid and microdialysate) of C14 ciprofloxacin (microdose)
timeFrame: Plasma sampling over 10 hours and microdialysate sampling.
measure: AUC (area under the curve in plasma, epithelial lining fluid and microdialysate) of C14 ciprofloxacin (carbon-14 radiolabelled compound, microdose)
timeFrame: Plasma sampling over 10 hours and microdialysate sampling.
measure: Tmax (time of peak concentration in plasma, epithelial lining fluid and microdialysate) of C14 ciprofloxacin (microdose)
timeFrame: Plasma sampling over 10 hours and microdialysate sampling.
measure: Cmax (peak concentration in microdialysate) of ciprofloxacin (macrodose)
timeFrame: Microdialysate sampling (Baseline sampling before study drug administration - sampling over 3 hours - retrodialysis)
measure: AUC (area under the concentration curve in microdialysate) of ciprofloxacin (macrodose)
timeFrame: Microdialysate sampling (Baseline sampling before study drug administration - sampling over 3 hours - retrodialysis)
measure: Tmax (time of peak concentration in microdialysate) of ciprofloxacin (macrodose)
timeFrame: Microdialysate sampling (Baseline sampling before study drug administration - sampling over 3 hours - retrodialysis)
Secondary outcomes:
measure: Incidence of Treatment Emergent Adverse Events
timeFrame: Screening visit and final examination are performed up to 7 days before/after the actual study day and safety and tolerability assessed.
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Medical University of Vienna
Study officials:
affiliation: Medical University of Vienna
name: Markus Zeitlinger, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.