Open-label, dose escalation phase I study in healthy volunteers to evaluate the safety and pharmacokinetics of a human monoclonal antibody to Clostridium difficile toxin A
Massachusetts Biologic Laboratories
Adult; Antibodies, Anti-Idiotypic; Antibodies, Bacterial; Antibodies, Monoclonal; effects; Antitoxins; Bacterial Toxins; Enterotoxins; Enzyme-Linked Immunosorbent Assay; Female; Half-Life; Humans; Infusions, Intravenous; Male; Middle Aged
Immunology and Infectious Disease
BACKGROUND: Recent data suggest that Clostridium difficile-associated diarrhea is becoming more severe and difficult to treat. Antibody responses to C. difficile toxin A are protective against symptomatic disease and recurrence. We examined the safety and pharmacokinetics (pk) of a novel neutralizing human monoclonal antibody against C. difficile toxin 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 20 mg/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: mean C(max) ranged from 6.82 microg/ml for the 0.3 mg/kg cohort to 511 microg/ml for the 20 mg/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. C(max) increased proportionally with increasing doses. A randomized study of CDA1 in patients with C. difficile associated diarrhea is underway.
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Citation: Vaccine. 2008 Jun 25;26(27-28):3404-9. Epub 2008 May 7. Link to article on publisher's site
DOI of Published Version
Taylor, Claribel P.; Tummala, Hemachand; Molrine, Deborah; Davidson, Lisa; Farrell, Richard J.; Lembo, Anthony J.; Hibberd, Patricia L.; Lowy, Israel; and Kelly, Ciaran P., "Open-label, dose escalation phase I study in healthy volunteers to evaluate the safety and pharmacokinetics of a human monoclonal antibody to Clostridium difficile toxin A" (2008). Open Access Articles. 2046.