Evaluating the Plasma, Epithelial Lining, and Alveolar Macrophage Concentrations of Intravenous Carbavance™ (RPX2014/RPX7009) in Healthy Adult Subjects

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 (RPX2014) plus a new beta-lactamase inhibitor (RPX7009) which has activity against serine beta-lactamases, including KPC. This Phase 1 study will assess the pharmacokinetics of intravenous RPX2014 and RPX7009 in plasma and epithelial fluid.

Inclusion criteria

• Healthy adult males and/or females, 18 to 55 years of age (inclusive) at the time of screening.
• Body mass index (BMI) ≥ 18.5 and ≤ 30 (kg/m2) and weight between 55.0 and 100.0 kg (inclusive) at the time of screening.
• Medically healthy with clinically insignificant screening results (e.g., laboratory profiles, medical histories, electrocardiograms (ECGs), physical examination) as deemed by the PI.
• Non-tobacco/nicotine-containing product users for a minimum of 6 months prior to Day 1.
• Voluntarily consent to participate in the study.

Exclusion criteria

• History or presence of significant oncologic, cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, or psychiatric disease.
• Positive urine drug/alcohol testing at screening (or Day -1).
• Positive testing for human immunodeficiency virus (HIV) or hepatitis B surface antigen (HBsAg).
• 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.).
• Clinically significant pulmonary or any other disease that prevents a subject from undergoing bronchoscopy with bronchopulmonary lavage.
• History of seizures (e.g., epilepsy), head injury or meningitis requiring ongoing anti-seizure medications.
• Use of any prescription medication (with the exception of hormonal contraceptives or hormone replacement therapy for females) within 14 days prior to Day 1.
• Participation in another investigational clinical trial within 30 days prior to Day 1.
• Females who are pregnant or lactating.
• Surgery within the past three months prior to Day 1 determined by the PI to be clinically relevant.
• Any acute illness including clinically significant infection within 30 days prior to Day 1.
• QTcF interval >450 msec, or history of prolonged QT syndrome at screening (or Day 1).
• Calculated creatinine clearance less than 80 mL/min (Cockroft-Gault method) at screening.
• Subjects who have any clinically significant abnormalities on laboratory values at screening (or Day -1), including:

• White blood cell count (WBC) < 3,000/mm3, hemoglobin < 11g/dL.
• Absolute neutrophil count < 1,200/mm3 or platelet count < 120,000/mm3.
• Liver function abnormalities at screening (or Day -1) (defined by an elevation in bilirubin, AST or ALT 1.5 x ULN of the normal range for subjects based on age and sex).