Evaluation of Innovative Tools in Development of Antibiotics

Study Overview
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Brief Summary
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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.

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

Conditions
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Pneumonia

Intervention / Treatment
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* Drug: Ciprofloxacin
* Drug: Imipenem


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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. |