Pharmacokinetics and Safety of Cefazolin 3gm DUPLEX in Adults

Study Overview
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Brief Summary
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This study is designed to evaluate the pharmacokinetics (PK) of a single 3 gm dose of cefazolin from a DUPLEX container, in adult subjects (weighing >/= 120 kg) scheduled for surgery. Cefazolin will be administered as a 30-minute intravenous (IV) infusion, per cefazolin Package Insert. Five PK samples per subject will be obtained up to 8 hours after dosing. These data will then be assessed by the validated Cefazolin PK Model to verify there are no significant PK changes within this study population.

Detailed Description
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This is a Phase 1, open-label, single-dose, multiple-center, study to determine the pharmacokinetics of a single 3 g dose of cefazolin administered as a 30 minute IV infusion prior to surgery in adult subjects weighing >/= 120 kg. Adult subjects will be enrolled in order to ensure at least 12 subjects complete the study. Enrollment will be competitive across the study sites. All subjects will have Screening and baseline evaluations performed to ensure their eligibility for the study The Screening Period is up to 30 days before administration of study drug on Day 1. Study drug will be administrated as an infusion over 30 minutes starting approximately 0.5 hours before surgery begins and following institutional guidelines on Day 1 (day of surgery). Planned surgical procedures may be performed outpatient or inpatient and are expected to last no longer than 3 hours. If the surgery is extended unexpectedly beyond the 3-hour limit, additional doses of study drug are permitted according to institutional guidelines. PK blood sample collection will continue after the administration of an additional dose of cefazolin. Safety in this population will also be assessed. All subjects will have five (5) individual whole blood samples (4 mL each) collected for the estimation of cefazolin concentration in plasma at the following times after the start of the infusion: 0.5 (+/-10 min) end of infusion, 1 h (+/-15 min), 2 h (+/-15 min), 4 h (+/-15 min) and 8 h (+/-15 min). Safety will be assessed by monitoring adverse events (AEs), physical examination, vital signs, and clinical laboratory tests. A follow-up visit will be performed on Day 8 (+/-1 day) for safety assessments. A subject is considered a study completer if he/she has completed all study related procedures through the end of surgery and the required PK sample collections. It is highly preferred that the subjects also participate in the Day 8 (+/-1 day) Safety Follow-up. For subjects who withdraw or are withdrawn before study completion of the study, every effort will be made to perform all Safety Follow up procedures. Any subject who withdraws or is withdrawn before collection of at least 4 of the 5 PK samples will not be consider as a PK completer. If necessary, additional subjects must be enrolled to ensure that there are at least 12 PK completers. On Day 8 (+/-1 day), a Safety follow-up will be conducted. If this is an in-person visit, the following will be performed: vital signs, clinical laboratory tests, examination of the infusion site, review of AEs and concomitant medication. If an in-person visit is not possible, every effort will be made to contact the subject by phone and the subjects will be asked about any AEs and concomitant medication they may have taken.

Official Title
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A Phase 1, Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics of a Single 3 Gram Dose of Cefazolin in Adult Subjects Weighing >= 120 kg Scheduled for Surgery

Conditions
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Infections

Intervention / Treatment
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* Drug: Cefazolin 3gm for Injection USP and Dextrose Injection USP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged >/= 18 years; Must weigh >/= 120 kg Able to understand and sign the Informed Consent Form(s) (ICF); Is scheduled for surgery that is expected to last less than 3 hours; Is scheduled for any type of surgery where a single-dose perioperative cefazolin prophylaxis is appropriate. Exclusion Criteria: If female, is pregnant or lactating/breastfeeding. If female that is of childbearing potential and sexually active, and is not using an effective method of birth control, e.g., oral contraceptives, double barrier methods, hormonal injectable or implanted contraceptives, tubal ligation, or have a partner with a vasectomy. Has a history of renal impairment -- Subject has an eGFR of <80 mL/min/1.73m2 performed at Screening as calculated by the following equation: 186 x (Creatinine/88.4)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if black) (FDA Guidance for Industry Pharmacokinetics in Patients with Impaired Renal Function) Has a known allergy or hypersensitivity to β lactam/cephalosporin antibiotics, corn products, or dextrose-containing products or solutions, or any of the other ingredients of Cefazolin for Injection United States Pharmacopeia (USP) and Dextrose Injection USP in DUPLEX. Has a result of any laboratory test (or repeat test, if done), obtained as standard of care, that is outside the normal limit of the site's laboratory reference range AND is considered by the investigator to be clinically significant. Has had a recent (within 14 days prior to the planned surgery) administration of cefazolin. Has had administration of any medication (e.g., prescription, herbal, over-the-counter medication[s] or dietary supplements) known to interact with cefazolin within 5 days prior to the study treatment administration. Has a known history of human immunodeficiency virus, hepatitis B, or hepatitis C infection. Has a current history of medical condition(s), which in the opinion of the investigator, would interfere with the evaluation of the study treatment. Has a known history of organ transplant. Has a clinically relevant disease/dysfunction of or a history of severe cardiac, pulmonary or hepatic disease. Is undergoing any cardiovascular procedure including, but not limited to, major cardiac surgery, cardiac catheterizations (including electrophysiology studies), ablations, automatic implantable cardioverter-defibrillator (AICD), and pacemaker. Has received any other investigational drug/device within 30 days prior to the study treatment administration. Has any planned medical intervention or personal event that might interfere with ability to comply with the study requirements. The subject has any condition that, in the opinion of the investigator, would compromise the safety of the subject or the quality of the data. Is unable or unwilling to adhere to the study-specified procedures and restrictions. Is an employee of the Sponsor, Investigator or study-center, has direct involvement in the study or other studies under the direction of that Investigator or study-center, or is a family member of the employees or the Investigator.

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: Prevention
Intervention Model: Single Group Assignment
Interventional Model Description: This is an open-label, non-randomized pharmacokinetic study. All subjects will be receiving the same study treatment, thus blinding is unnecessary.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cefazolin 3gm Injection<br>Study drug will be administrated as an infusion over 30 minutes starting approximately 0.5 hours before surgery begins and following institutional guidelines on Day 1 (day of surgery). All subjects will have five (5) individual whole blood samples (4 mL each) collected for the estimation of cefazolin concentration in plasma at the following times after the start of the infusion: 0.5 (+/-10 min) end of infusion, 1 h (+/-15 min), 2 h (+/-15 min), 4 h (+/-15 min), and 8 h (+/-15 min). | Drug: Cefazolin 3gm for Injection USP and Dextrose Injection USP<br>* Cefazolin 3gm for Injection USP and Dextrose Injection USP in the DUPLEX® Drug Delivery System. Administration will occur once as a 30 minute IV infusion prior to surgery in adult subjects weighing >/= 120 kg<br>* Other names: Cefazolin 3gm in DUPLEX (50ml);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cefazolin plasma concentration following infusion | Concentrations will be determined through analysis of 5 blood samples drawn at 0.5 (end of infusion), 1, 2, 4, and 8 hours after the start of study drug infusion. | 8 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Treatment-Emergent Adverse Events [Safety] according to Study Protocol | Safety will be assessed by monitoring adverse events (AEs), physical examination, vital signs, and clinical laboratory tests. | 2 days with optional visit on Day 8 | 
| Hematology: Hemoglobin (Hb) | gm/dL | 2 days with optional visit on Day 8 | 
| Hematology: Hematocrit (Hct) |  | 2 days with optional visit on Day 8 | 
| Hematology: mean corpuscular volume (MCV) | fL | 2 days with optional visit on Day 8 | 
| Hematology: mean corpuscular hemoglobin (MCH) | pg | 2 days with optional visit on Day 8 | 
| Hematology: mean corpuscular hemoglobin concentration | mmol/L | 2 days with optional visit on Day 8 | 
| Hematology: Platelet count | platelets/mcL | 2 days with optional visit on Day 8 | 
| Hematology: RBC | cells/mcL | 2 days with optional visit on Day 8 | 
| Hematology: WBC with Differential | cells/mcL | 2 days with optional visit on Day 8 | 
| Clinical Chemistry: Sodium | mmol/L | 2 days with optional visit on Day 8 | 
| Clinical Chemistry: Potassium | mmol/L | 2 days with optional visit on Day 8 | 
| Clinical Chemistry: Chloride | mmol/L | 2 days with optional visit on Day 8 | 
| Clinical Chemistry: CO2 | mmol/L | 2 days with optional visit on Day 8 | 
| Clinical Chemistry: Glucose | mg/dL | 2 days with optional visit on Day 8 | 
| Clinical Chemistry: ALT | U/L | 2 days with optional visit on Day 8 | 
| Clinical Chemistry: AST | U/L | 2 days with optional visit on Day 8 | 
| Clinical Chemistry: Creatine phosphokinase (CPK) | Units/L | 2 days with optional visit on Day 8 | 
| Clinical Chemistry: Lactic acid dehydrogenase (LDH) | Units/L | 2 days with optional visit on Day 8 | 
| Clinical Chemistry: Albumin | g/L | 2 days with optional visit on Day 8 | 
| Clinical Chemistry: Alkaline phosphatase | U/L | 2 days with optional visit on Day 8 | 
| Clinical Chemistry: Uric Acid | mmol/L | 2 days with optional visit on Day 8 | 
| Clinical Chemistry: Calcium | mmol/L | 2 days with optional visit on Day 8 | 
| Clinical Chemistry: Phosphate | U/L | 2 days with optional visit on Day 8 | 
| Clinical Chemistry: Total protein | g/L | 2 days with optional visit on Day 8 | 
| Clinical Chemistry: Total bilirubin | micro-mol/L | 2 days with optional visit on Day 8 | 
| Clinical Chemistry: Blood urea nitrogen | mmol/L | 2 days with optional visit on Day 8 | 
| Clinical Chemistry: Creatinine | micro-mol/L | 2 days with optional visit on Day 8 | 
| Vital Signs: Temperature | Degree centigrade | 2 days with optional visit on Day 8 | 
| Vital Signs: Blood Pressure (Systolic/Diastolic) | mm Hg | 2 days with optional visit on Day 8 | 
| Vital Signs: Heart Rate | Beats per minute | 2 days with optional visit on Day 8 | 
| Vital Signs: Respiratory Rate | Breaths per minute | 2 days with optional visit on Day 8 | 
| Vital Signs: Weight | kg | 2 days with optional visit on Day 8 | 
| Vital Signs: Height | cm | 2 days with optional visit on Day 8 | 
| Vital Signs: BMI | kg/cm^2 | 2 days with optional visit on Day 8 | 
| ECG: PR Interval | sec | 2 days | 
| ECG: QRS Duration | sec | 2 days | 
| ECG: QT Interval | sec | 2 days | 
| Urine Pregnancy Test | (If appropriate) If positive, a confirmatory serum test will be performed. | 2 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cephalosporin, antibiotic, infection control, surgical prophylaxis