Pharmacokinetic and Safety Study of HYLENEX Recombinant-Augmented Subcutaneous Ceftriaxone Administration (INFUSE-Cftrx)

• AUC0-t [ Time Frame: Start of ceftriaxone administration through time of last measureable plasma ceftriaxone concentration ] [ Designated as safety issue: No ]
  Area under the drug concentration-time curve from time zero to the time of the last measurable concentration (calculated by the linear trapezoidal method)
• AUC0-inf [ Time Frame: from the start of ceftriaxone administration to infinity ] [ Designated as safety issue: No ]
  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)

• Comparison of the pharmacokinetic parameters for ceftriaxone after subcutaneous administration, with and without HYLENEX recombinant, and after IV administration [ Time Frame: 48 hours ]
• Safety and tolerability (injection site reactions, adverse events, physical examinations, vital signs) of subcutaneous administration of ceftriaxone, with and without HYLENEX recombinant [ Time Frame: 7 days ]

• Cmax [ Time Frame: at the time of the highest measured plasma ceftriaxone concentration ] [ Designated as safety issue: No ]
  Maximum measured plasma ceftriaxone concentration
• Tmax [ Time Frame: from start of ceftriaxone administration until time of maximum measured plasma ceftriaxone concentration ] [ Designated as safety issue: No ]
  Time to maximum measured plasma ceftriaxone concentration

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.

• Drug: SC HYLENEX and Ceftriaxone
  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)
  Other Names:

  • HYLENEX recombinant
  • hyaluronoglucosaminidase
  • hyaluronidase
  • rHuPH20
• Drug: SC Placebo and Ceftriaxone
  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)
  Other Names:

  • saline
  • normal saline
  • 0.9% sodium chloride injection
• Drug: IV Ceftriaxone
  single, intravenous infusion of 1 gm ceftriaxone (40 mg/mL solution administered at 0.83 mL/min over 30 minutes)
  Other Name: ceftriaxone

• Experimental: HYLENEX SC, Placebo SC, IV
  subcutaneous HYLENEX and ceftriaxone as 1st intervention, subcutaneous placebo and ceftriaxone as 2nd intervention, IV ceftriaxone as 3rd intervention
  Interventions:

  • Drug: SC HYLENEX and Ceftriaxone
  • Drug: SC Placebo and Ceftriaxone
  • Drug: IV Ceftriaxone
• Experimental: HYLENEX SC, IV, Placebo SC
  subcutaneous HYLENEX and ceftriaxone as 1st intervention, IV ceftriaxone as 2nd intervention, subcutaneous placebo and ceftriaxone as 3rd intervention
  Interventions:

  • Drug: SC HYLENEX and Ceftriaxone
  • Drug: SC Placebo and Ceftriaxone
  • Drug: IV Ceftriaxone
• Experimental: Placebo SC, HYLENEX SC, IV
  subcutaneous placebo and ceftriaxone as 1st intervention, subcutaneous HYLENEX and ceftriaxone as 2nd intervention, IV ceftriaxone as 3rd intervention
  Interventions:

  • Drug: SC HYLENEX and Ceftriaxone
  • Drug: SC Placebo and Ceftriaxone
  • Drug: IV Ceftriaxone
• Experimental: Placebo SC, IV, HYLENEX SC
  subcutaneous placebo and ceftriaxone as 1st intervention, IV ceftriaxone as 2nd intervention, subcutaneous HYLENEX and ceftriaxone as 3rd intervention
  Interventions:

  • Drug: SC HYLENEX and Ceftriaxone
  • Drug: SC Placebo and Ceftriaxone
  • Drug: IV Ceftriaxone
• Experimental: IV, HYLENEX SC, Placebo SC
  IV ceftriaxone as 1st intervention, subcutaneous HYLENEX and ceftriaxone as 2nd intervention, subcutaneous placebo and ceftriaxone as 3rd intervention
  Interventions:

  • Drug: SC HYLENEX and Ceftriaxone
  • Drug: SC Placebo and Ceftriaxone
  • Drug: IV Ceftriaxone
• Experimental: IV, Placebo SC, HYLENEX SC
  IV ceftriaxone as 1st intervention, subcutaneous placebo and ceftriaxone as 2nd intervention, subcutaneous HYLENEX and ceftriaxone as 3rd intervention
  Interventions:

  • Drug: SC HYLENEX and Ceftriaxone
  • Drug: SC Placebo and Ceftriaxone
  • Drug: IV Ceftriaxone

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