A Safety and Pharmacokinetic Study of Fidaxomicin in Children with Clostridium difficile-associated diarrhea
Method: This open-label study enrolled children, ages 6 mo to <18 yr, with diarrhea + positive toxin. Subjects were treated with FDX for 10 days with 32 mg/kg /day (up to 200 mg BID, the adult dose), as either the commercial tablet or an oral suspension. Plasma samples for drug concentration measurement were collected pre-dose and at two timepoints post-dose between days 5-10. Fecal samples were collected on the last day of therapy. Safety was assessed via adverse events, clinical labs, ECGs, physical exams including vital signs. Efficacy was also monitored.
Result: 38 subjects, range 11 mo to 17 yr of age, were enrolled and treated. Most had relatively complex medical histories, including neoplasms (23.7%) and gastrointestinal disorders (78.9%). Plasma concentrations were generally in the low ng/mL range, with a mean FDX concentration across the strata that ranged from 8.87 to 16.6 ng/mL and metabolite OP-1118 that ranged from 27.5 to 130 ng/mL at 1-2 hours post-dose, with no age-related trends. Fecal FDX concentrations averaged 3230 µg/g, with a trend toward higher concentrations in the youngest age group. 73.7% of subjects had at least one adverse event, with most adverse events being mild (44.7%) to moderate (21.1%) in severity and were of the nature expected for a pediatric population with moderate to severe underlying illnesses. 9 subjects had SAEs, none of which were considered related to FDX. Clinical response rates were high (92.1% overall). 28.6% of the subjects with a clinical response recurred; of these, all but one had a history of recurrent CDAD.
Conclusion: Fidaxomicin treatment in children with CDAD was well tolerated, and had a pharmacokinetic profile that was similar to that reported in adults, with low plasma levels and high fecal concentrations. Clinical response was excellent, and while a higher percentage of children experienced a recurrence than observed in prior adult studies, this is likely reflective of the high number of subjects enrolling with prior episodes of CDAD.
Cubist Pharmaceuticals: Employee, Salary
M. Michaels, Cubist Pharmaceuticals: Investigator, Investigator fees
S. Flanagan, Cubist: Employee and Shareholder, Salary
M. O'gorman, Cubist Pharmaceuticals: Investigator, Investigator fees