Safety Study of Intravenous Biapenem (RPX2003) and RPX7009 Given Alone and in Combination

Phase 1

Completed

Lead Sponsor: Rempex Pharmaceuticals (a wholly owned subsidiary of The Medicines Company)

Brief Summary: RPX7009 (beta-lactamase inhibitor) is being studies in combination with a carbapenem biapenem to treat bacterial infections, including those due to multi-drug resistant bacteria.

Detailed Description: The worldwide spread of resistance to antibiotics among Gram-negative bacteria, particularly members of the ESKAPE group of pathogens, has resulted in a crisis in the treatment of hospital acquired infections. In particular, the recent dissemination of a serine carbapenemase (e.g., KPC) in Enterobacteriaceae in US hospitals now poses a considerable threat to the carbapenems and other members of the beta-lactam class of antimicrobial agents.

Rempex is developing a fixed combination antibiotic of a carbapenem (RPX2003 or biapenem) plus a new beta-lactamase inhibitor (RPX7009) which has activity against serine beta-lactamases, including KPC. This Phase 1 study will assess the safety, tolerability and pharmacokinetics and pharmacodynamics of Intravenous Biapenem and RPX7009, administered alone and in combination in healthy adult subjects.

Recruitment & Eligibility

Inclusion Criteria

Healthy adult males and/or females, 18 to 55 years of age
Body mass index (BMI) ≥ 18.5 and ≤ 29.9 (kg/m2) and weight between 55.0 and 100.0 kg (inclusive).
Medically healthy with clinically insignificant screening results
Non-tobacco/nicotine-containing product users for a minimum of 6 months prior to Day 1.
Sexually abstinent or use acceptable methods of birth control

Exclusion Criteria

History or presence of significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, or psychiatric disease.
History or presence of alcoholism or drug abuse within the 2 years prior to Day 1.
Hypersensitivity or idiosyncratic reaction to beta-lactam antibiotics (e.g. penicillins, cephalosporins, carbapenems, etc.).
Use of any over-the-counter (OTC) medication, including herbal products and vitamins, within the 7 days prior to Day 1. Up to 2 grams per day of acetaminophen is allowed for acute events at the discretion of the PI.
Plasma donation within 7 days prior to Day 1.
Subjects who have any abnormalities on laboratory values at screening or check-in (Day -1).

Arm && Interventions

Group	Intervention	Description
Normal saline	Normal saline	Single and multiple dose of normal saline
Single dose IV of biapenem or RPX7009	RPX7009	Single dose IV infusion of biapenem or RPX7009
Single dose IV of biapenem or RPX7009	Biapenem	Single dose IV infusion of biapenem or RPX7009
Single dose of biapenem or RPX7009	RPX7009	Single IV dose of biapenem or RPX7009 (for those on active drug, this will be the drug not given in the first IV treatment)
Biapenem and RPX7009 in combination	RPX7009	Single dose followed by a multiple dose of biapenem and RPX7009 in combination
Single dose of biapenem or RPX7009	Biapenem	Single IV dose of biapenem or RPX7009 (for those on active drug, this will be the drug not given in the first IV treatment)
Biapenem and RPX7009 in combination	Biapenem	Single dose followed by a multiple dose of biapenem and RPX7009 in combination

Primary Outcome Measures

Name	Time	Method
Safety from baseline to the end of the study	Day 1 - Day 17	Number of patients with adverse events; assessed by patient reporting, collection of vital signs, ECGs and absolute values and changes over time of hematology, chemistry and urinalysis.

Secondary Outcome Measures

Name	Time	Method
Composite of Pharmacokinetic (PK) parameters of RPX7009, biapenem & the combination following ascending single and multiple dose administration.	Day 1 - Day 14	Comparison will be performed between the cohorts for the plasma AUC0-t, AUC0-inf, Cmax, and Tmax. Urine PK parameters such as amount excreted and % dose excreted will be calculated from urinary excretion data.
Composite of Pharmacodynamic (PD) parameters of RPX7009, biapenem & the combination following ascending single and multiple dose administration.	Days 1-14	Serum for bactericidal titers (SBT) assessments will be collected on Days 1, 4, 7 and 14 (at the end-of-infusion (EOI)), and at 2, 4, and 8 hours after start of infusion.