Open-label, dose escalation phase I study in healthy volunteers to evaluate the safety and pharmacokinetics of a human monoclonal antibody toClostridium difficiletoxin A

• Published in: Vaccine 2008-06, Vol.26 (27-28), p.3404
• Main Authors: Taylor, Claribel P, Tummala, Sanjeev, Molrine, Deborah, Davidson, Lisa, Farrell, Richard J, Lembo, Anthony, Hibberd, Patricia L, Lowy, Israel, Kelly, Ciaran P
• Format: Article
• Language: English
• Subjects: Blood pressure; Diarrhea; Drug therapy; Good Manufacturing Practice; Hospitals; Immunoassays; Laboratories; Pharmacokinetics; Safety
• ISSN: 0264-410X; 1873-2518
• DOI: 10.1016/j.vaccine.2008.04.042

Background Recent data suggest thatClostridium difficile-associated diarrhea is becoming more severe and difficult to treat. Antibody responses toC. difficiletoxin A are protective against symptomatic disease and recurrence. We examined the safety and pharmacokinetics (pk) of a novel neutralizing human monoclonal antibody againstC. difficiletoxin A (CDA1) in healthy adults. Methods Five cohorts with 6 subjects each received a single intravenous infusion of CDA1 at escalating doses of 0.3, 1, 5, 10, and 20mg/kg. Safety evaluations took place on days 1, 2, 3, 7, 14, 28, and 56 post-infusion. Samples for pk analysis were obtained before and after infusion, and at each safety evaluation. Serum CDA1 antibody concentrations and human anti-human antibody (HAHA) titers were measured with enzyme-linked immunosorbent assays. A noncompartmental model was used for pk analysis. Results Thirty subjects were enrolled. The median age was 27.5 yrs. There were no serious adverse events (AE) related to CDA1. Twenty-one of the 48 reported non-serious adverse events were possibly related to CDA1, and included transient blood pressure changes requiring no treatment, nasal congestion, headache, abdominal cramps, nausea, and self-limited diarrhea. Serum CDA1 concentrations increased with escalating doses: meanCmaxranged from 6.82μg/ml for the 0.3mg/kg cohort to 511μg/ml for the 20mg/kg cohort. The geometric mean values of the half-life of CDA1 ranged between 25.3 and 31.8 days, and the volume of distribution approximated serum. No subject formed detectable HAHA titers. Conclusion Administration of CDA1 as a single intravenous infusion was safe and well tolerated.Cmaxincreased proportionally with increasing doses. A randomized study of CDA1 in patients withC. difficileassociated diarrhea is underway.