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

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 postinfusion. Samples for pk analysis were obtained before and after infusion, and at each safety evaluation. Serum CDAI 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 CDAI. Twenty-one of the 48 reported non-serious adverse events were possibly related to CDAI, and included transient blood pressure changes requiring no treatment, nasal congestion, headache, abdominal cramps, nausea, and self-limited diarrhea. Serum CDAI concentrations increased with escalating doses: mean C a ranged from 6.82 l.Lg/mI for the 0.3 mg/kg cohort to 511 [Lg/mI for the 20 mg/kg cohort. The geometric mean values of the half-life of CDAI 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. Cmax increased proportionally with increasing doses. A randomized study of CDA1 in patients with C. difficile associated diarrhea is underway.