Crossover Study to Compare the Pharmacokinetics of Subcutaneous and Intravenous Ceftriaxone Administration

Study Overview
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Brief Summary
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The proposed study aims to assess the time above MIC (4 mg/mL), and the pharmacokinetics/pharmacodynamics and bioavailability of 1 g ceftriaxone administered by constant rate subcutaneous infusion over 2 hours compared with 1 g of ceftriaxone administered as a constant IV infusion over 0.5 hours. In addition, the study will compare the results obtained after 1 g ceftriaxone intravenous or subcutaneous administration with 2 g ceftriaxone administered subcutaneously

Official Title
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A Single-Dose, Randomized, Three-way, Partially Blinded Crossover Study to Compare the Pharmacokinetics and Bioavailability of Ceftriaxone Administered as a 1 Gram Intravenous Infusion, a 1 Gram Subcutaneous Infusion and a 2 Gram Subcutaneous Infusion in Healthy Adult Subjects

Conditions
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Pharmacokinetics in Healthy Adults

Intervention / Treatment
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* Drug: ceftriaxone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: An Institutional Review Board (IRB) approved informed consent is signed and dated prior to any study-related activities. Male and female subjects between 18 and 65 years of age inclusive. Subjects must have body weight of 45.5 to 105 kg inclusive and body mass index (BMI) ≤34 kg/m2. Females will be non-pregnant, non-lactating, and either post-menopausal for at least 1 year, surgically sterile (e.g., tubal ligation, hysterectomy) for at least 90 days, or agree, from the time of signing the informed consent or 14 days prior to Baseline until Follow-up, to use TWO (2) of the following forms of contraception: a IUD with spermicide, female condom with spermicide, contraceptive sponge with spermicide, an intravaginal system, diaphragm with spermicide, cervical cap with spermicide, a male sexual partner who agrees to use a male condom with spermicide, a sterile sexual partner, OR abstinence. For all females, a pregnancy test result must be negative at Screening and Baseline/Day 0 Males agree from the time of Baseline/Day 0 until Follow-up, to use TWO (2) forms of contraception: ONE must be a male condom with spermicide; the second may be ONE of the following: his female partner uses either an IUD with spermicide, female condom with spermicide, contraceptive sponge with spermicide, an intravaginal system, diaphragm with spermicide, cervical cap with spermicide, oral contraceptives; OR abstinence Subject has normal (or abnormal and clinically insignificant) laboratory values at screening. Subject is medically normal with no significant abnormal findings at the Baseline physical examination. Subjects must have Baseline values of the following laboratory tests as specified: AST, ALT, alkaline phosphatase (ALP), total bilirubin, and creatinine <1.1 ULN Platelet count >100 X 103/µL Neutrophil count >1.0 X 103/µL Subject has the ability to understand the requirements of the study and is willing to comply with all study procedures. Subject has not consumed and agrees to abstain from taking any vitamin or dietary supplements or non-prescription drugs (except as authorized by the Investigator and Medical Monitor) for 3 days prior to CRU admission through Follow-Up, with the exception of oral contraceptives. Subject has not consumed and agrees to abstain from taking any prescription drugs (except as authorized by the Investigator and Medical Monitor) during the 14 days prior to CRU admission through Follow-Up. Subject has not consumed and agrees to abstain from consuming grapefruit, grapefruit juice, or juices containing grapefruit, or Seville oranges during the 3 days prior to CRU admission through Follow-Up. Subject agrees to abstain from using alcohol from 48 hours prior to Screening and CRU admission through CRU discharge for each period. Exclusion Criteria: Evidence of or history of clinically significant oncologic, pulmonary, hepatic, gastrointestinal, cardiovascular, hematologic, metabolic, neurological, immunologic, nephrologic, endocrine, or psychiatric disease, or current clinically significant infection. History of chronic skin conditions requiring medical therapy. Clinically significant abnormalities at Screening or Baseline in safety laboratory tests. Corrected QT interval (QTc) greater than 450 msec for males and 470 msec for females as corrected by the Fridericia formula. Major surgery within 30 days prior to Screening. Administration of an investigational drug or implantation of investigational device, or participation in another trial, within 30 days prior to Screening. Any surgical or medical condition which in the opinion of the investigator may interfere with participation in the study or which may affect the outcome of the study. Positive test for hepatitis B, hepatitis C, or HIV at Screening. Positive urine drug screen at Screening or Baseline. Tobacco users (includes users who stopped smoking £90 days prior to the screening evaluation). [Note: Tobacco use includes smoking and the use of snuff and chewing tobacco, and other nicotine or nicotine containing products.] History of alcohol abuse within 6 months prior to screening, as determined by the Investigator. Consumed alcohol within 48 hours of Screening or each CRU admission or have a positive alcohol test at Screening or any admission to the CRU. Known allergy cephalosporin class of antibiotics or penicillin. Female subject who is pregnant or lactating. Donation of greater than 100 mL of either whole blood or plasma within 30 days prior to study drug administration. Subjects with hemoglobin (Hb) ≤10.5 g/dL

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: IV ceftriaxone (0.5hr) 1 gm<br>ceftriaxone for injection, (total dose = 1.0 g) administered IV over 30 minutes via infusion pump (Open Label) | Drug: ceftriaxone<br> <br> |
| Experimental: subcutaneous ceftriaxone, (2hr), 1 gm<br>ceftriaxone for injection, (total dose = 1.0 g) administered subcutaneous over 2 hours (Blinded). | Drug: ceftriaxone<br> <br> |
| Experimental: subcutaneous ceftriaxone, (2 hr), 2 gm<br>ceftriaxone for injection, (total dose = 2.0 g) administered subcutaneous over 2 hours (Blinded). | Drug: ceftriaxone<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration | Cmax, observed by inspection of individual study participant plasma concentration time plots. | 48 hours | 
| Time of observed maximum plasma concentration | Tmax, obtained directly from the observed concentration-time data | 48 hours | 
| Area under the plasma concentration-time curve | AUClast: AUC from time 0 to the last measureable non-zero concentration, calculated by a combination of linear and logarithmic trapezoidal methods | 48 hours | 
| Area under the concentration time curve, extrapolated to infinity | AUCinf: Area under the concentration time curve from time 0 extrapolated to infinity, calculated as AUClast + Clast/λz | 48 hours | 
| Terminal phase elimination rate constant | Terminal phase elimination rate constant, estimated by linear regression of logarithmically transformed concentration versus time data. | 48 hours | 
| Terminal phase half life | Terminal phase half life, estimated using the equation [ln(2)/λz] | 48 hours |