Pharmacokinetic and Safety Study of HYLENEX Recombinant-Augmented Subcutaneous Ceftriaxone Administration

Study Overview
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Brief Summary
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The objectives of this study are: to establish the safety of subcutaneous administration of ceftriaxone at different concentrations, with and without HYLENEX recombinant, and to determine the maximum tolerated concentration; and to establish the pharmacokinetic comparability of subcutaneous administration of ceftriaxone with HYLENEX recombinant to subcutaneous administration without HYLENEX recombinant and to IV administration.

Official Title
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INcreased Flow Utilizing Subcutaneously-Enabled Ceftriaxone (INFUSE-Ceftriaxone) Study: A Phase I Study Comparing the Safety and Pharmacokinetics of Ceftriaxone Administered Subcutaneously With and Without Human Recombinant Hyaluronidase (HYLENEX Recombinant) and Intravenously in Human Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Drug: SC HYLENEX and Ceftriaxone
* Drug: SC Placebo and Ceftriaxone
* Drug: IV Ceftriaxone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 18-65 years of age If female: non-lactating; non-pregnant; and incapable of becoming pregnant, or taking specific precautions to avoid becoming pregnant before and during study Normal clinical laboratory parameters Adequate venous access in both upper extremities Agreeing to refrain from smoking and from ingesting any alcohol or caffeine-containing products before and during the study Good health based on medical history, physical examination and laboratory tests Non-smoking; or smoking less than 10 cigarettes per day and willing to refrain from use of nicotine products before and during study Exclusion Criteria: Received a cephalosporin within the 21 days prior to study or anticipated to receive non-study cephalosporin during study Pregnant or breast-feeding. Previously exposed to a hyaluronidase drug product Medical condition presenting unacceptable safety risk or likely to prevent completion of study Known hypersensitivity to hyaluronidase or any other ingredient in HYLENEX recombinant Contraindication to ceftriaxone, including known allergy to beta-lactam antibiotics Local condition precluding subcutaneous injection or injection site evaluation History of gastrointestinal disease (in particular colitis) Consumption of caffeine- or other methylxanthine-containing beverage within 24 hours before and/or during the PK sampling period Participation in study of any investigational drug or device within 30 days before this study Serum hemoglobin <12 g/dL. Blood donation or significant loss of blood within 56 days, or plasma donation within 7 days, prior to study Medical history/condition, screening physical examination finding or clinical laboratory result precluding safe participation in study, or which might adversely effect interpretation of study results History of drug or alcohol abuse within 2 years prior to study

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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HYLENEX SC, Placebo SC, IV<br>subcutaneous HYLENEX and ceftriaxone as 1st intervention, subcutaneous placebo and ceftriaxone as 2nd intervention, IV ceftriaxone as 3rd intervention | Drug: SC HYLENEX and Ceftriaxone<br>* single, subcutaneous, 150 U dose of HYLENEX; followed by single, subcutaneous, 1 gm dose of ceftriaxone (350 mg/mL solution administered at 2.5 mL/min over 1.14 minutes)<br>* Other names: rHuPH20;Drug: SC Placebo and Ceftriaxone<br>* single, subcutaneous injection of 1 mL 0.9% sodium chloride solution; followed by single, subcutaneous, 1 gm dose of ceftriaxone (350 mg/mL solution administered at 2.5 mL/min over 1.14 minutes)<br>* Other names: 0.9% sodium chloride injection;Drug: IV Ceftriaxone<br>* single, intravenous infusion of 1 gm ceftriaxone (40 mg/mL solution administered at 0.83 mL/min over 30 minutes)<br>* Other names: ceftriaxone;|
| Experimental: HYLENEX SC, IV, Placebo SC<br>subcutaneous HYLENEX and ceftriaxone as 1st intervention, IV ceftriaxone as 2nd intervention, subcutaneous placebo and ceftriaxone as 3rd intervention | Drug: SC HYLENEX and Ceftriaxone<br>* single, subcutaneous, 150 U dose of HYLENEX; followed by single, subcutaneous, 1 gm dose of ceftriaxone (350 mg/mL solution administered at 2.5 mL/min over 1.14 minutes)<br>* Other names: rHuPH20;Drug: SC Placebo and Ceftriaxone<br>* single, subcutaneous injection of 1 mL 0.9% sodium chloride solution; followed by single, subcutaneous, 1 gm dose of ceftriaxone (350 mg/mL solution administered at 2.5 mL/min over 1.14 minutes)<br>* Other names: 0.9% sodium chloride injection;Drug: IV Ceftriaxone<br>* single, intravenous infusion of 1 gm ceftriaxone (40 mg/mL solution administered at 0.83 mL/min over 30 minutes)<br>* Other names: ceftriaxone;|
| Experimental: Placebo SC, HYLENEX SC, IV<br>subcutaneous placebo and ceftriaxone as 1st intervention, subcutaneous HYLENEX and ceftriaxone as 2nd intervention, IV ceftriaxone as 3rd intervention | Drug: SC HYLENEX and Ceftriaxone<br>* single, subcutaneous, 150 U dose of HYLENEX; followed by single, subcutaneous, 1 gm dose of ceftriaxone (350 mg/mL solution administered at 2.5 mL/min over 1.14 minutes)<br>* Other names: rHuPH20;Drug: SC Placebo and Ceftriaxone<br>* single, subcutaneous injection of 1 mL 0.9% sodium chloride solution; followed by single, subcutaneous, 1 gm dose of ceftriaxone (350 mg/mL solution administered at 2.5 mL/min over 1.14 minutes)<br>* Other names: 0.9% sodium chloride injection;Drug: IV Ceftriaxone<br>* single, intravenous infusion of 1 gm ceftriaxone (40 mg/mL solution administered at 0.83 mL/min over 30 minutes)<br>* Other names: ceftriaxone;|
| Experimental: Placebo SC, IV, HYLENEX SC<br>subcutaneous placebo and ceftriaxone as 1st intervention, IV ceftriaxone as 2nd intervention, subcutaneous HYLENEX and ceftriaxone as 3rd intervention | Drug: SC HYLENEX and Ceftriaxone<br>* single, subcutaneous, 150 U dose of HYLENEX; followed by single, subcutaneous, 1 gm dose of ceftriaxone (350 mg/mL solution administered at 2.5 mL/min over 1.14 minutes)<br>* Other names: rHuPH20;Drug: SC Placebo and Ceftriaxone<br>* single, subcutaneous injection of 1 mL 0.9% sodium chloride solution; followed by single, subcutaneous, 1 gm dose of ceftriaxone (350 mg/mL solution administered at 2.5 mL/min over 1.14 minutes)<br>* Other names: 0.9% sodium chloride injection;Drug: IV Ceftriaxone<br>* single, intravenous infusion of 1 gm ceftriaxone (40 mg/mL solution administered at 0.83 mL/min over 30 minutes)<br>* Other names: ceftriaxone;|
| Experimental: IV, HYLENEX SC, Placebo SC<br>IV ceftriaxone as 1st intervention, subcutaneous HYLENEX and ceftriaxone as 2nd intervention, subcutaneous placebo and ceftriaxone as 3rd intervention | Drug: SC HYLENEX and Ceftriaxone<br>* single, subcutaneous, 150 U dose of HYLENEX; followed by single, subcutaneous, 1 gm dose of ceftriaxone (350 mg/mL solution administered at 2.5 mL/min over 1.14 minutes)<br>* Other names: rHuPH20;Drug: SC Placebo and Ceftriaxone<br>* single, subcutaneous injection of 1 mL 0.9% sodium chloride solution; followed by single, subcutaneous, 1 gm dose of ceftriaxone (350 mg/mL solution administered at 2.5 mL/min over 1.14 minutes)<br>* Other names: 0.9% sodium chloride injection;Drug: IV Ceftriaxone<br>* single, intravenous infusion of 1 gm ceftriaxone (40 mg/mL solution administered at 0.83 mL/min over 30 minutes)<br>* Other names: ceftriaxone;|
| Experimental: IV, Placebo SC, HYLENEX SC<br>IV ceftriaxone as 1st intervention, subcutaneous placebo and ceftriaxone as 2nd intervention, subcutaneous HYLENEX and ceftriaxone as 3rd intervention | Drug: SC HYLENEX and Ceftriaxone<br>* single, subcutaneous, 150 U dose of HYLENEX; followed by single, subcutaneous, 1 gm dose of ceftriaxone (350 mg/mL solution administered at 2.5 mL/min over 1.14 minutes)<br>* Other names: rHuPH20;Drug: SC Placebo and Ceftriaxone<br>* single, subcutaneous injection of 1 mL 0.9% sodium chloride solution; followed by single, subcutaneous, 1 gm dose of ceftriaxone (350 mg/mL solution administered at 2.5 mL/min over 1.14 minutes)<br>* Other names: 0.9% sodium chloride injection;Drug: IV Ceftriaxone<br>* single, intravenous infusion of 1 gm ceftriaxone (40 mg/mL solution administered at 0.83 mL/min over 30 minutes)<br>* Other names: ceftriaxone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-t | Area under the drug concentration-time curve from time zero to the time of the last measurable concentration (calculated by the linear trapezoidal method) | Start of ceftriaxone administration through time of last measureable plasma ceftriaxone concentration | 
| AUC0-inf | Area under the drug concentration-time curve from time zero to infinity, calculated as AUC0-t + Ct/kel (Ct = time of last measurable concentration; kel = terminal elimination rate constant) | from the start of ceftriaxone administration to infinity | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | Maximum measured plasma ceftriaxone concentration | at the time of the highest measured plasma ceftriaxone concentration | 
| Tmax | Time to maximum measured plasma ceftriaxone concentration | from start of ceftriaxone administration until time of maximum measured plasma ceftriaxone concentration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ceftriaxone, cephalosporins, pharmacokinetics, subcutaneous, hyaluronoglucosaminidase, hyaluronidase, hyaluronan, rHuPH20