title: 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.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Beth Israel Deaconess Medical Center, University of Massachusetts Medical School, Boston, Massachusetts, USA.
authors.forename: Claribel P
authors.initials: CP
authors.lastname: Taylor
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Tummala
authors.forename: Deborah
authors.initials: D
authors.lastname: Molrine
authors.forename: Lisa
authors.initials: L
authors.lastname: Davidson
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Farrell
authors.forename: Anthony
authors.initials: A
authors.lastname: Lembo
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Hibberd
authors.forename: Israel
authors.initials: I
authors.lastname: Lowy
authors.forename: Ciaran P
authors.initials: CP
authors.lastname: Kelly
mesh_terms: D000328:Adult; D000888:Antibodies, Anti-Idiotypic / Q000097:blood; D000907:Antibodies, Bacterial / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000992:Antitoxins / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors*; D004768:Enterotoxins / Q000037:antagonists & inhibitors*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D000992:Antitoxins; D001427:Bacterial Toxins; D004768:Enterotoxins; C041348:tcdA protein, Clostridium difficile