Objectives: Nitazoxanide (N) is a new broad-spectrum intestinal antiparasitic agent. Deacetyl-N or tizoxanide (T) and its glucuronide (TG) are the major circulating metabolites after oral administration of N. The objectives of this phase IB study were to assess the tolerability and to determine the phannacokinetics of T and TG after 7 days of 0.5 g and 1 g b.i.d. dosing of N in healthy volunteer subjects.
Methods: Sixteen healthy male volunteers were randomly assigned to 1 of 2 treatment groups. In each group, 2 subjects received a placebo and 6 received a single oral dose of 0.5 or 1 g of N followed by 7 days of b.i.d. dosing. Blood samples were collected during the first and last dosing intervals for plasma determination of T and TG. General tolerability, adverse reactions, ECG, vital signs and laboratory tests were recorded before and during treatment days.
Results: The 0.5 g b.i.d. dose was well-tolerated with only mild adverse events not differing significantly from the placebo. The 1 g b.i.d. dose was associated with an increased frequency of gastrointestinal side effects, primarily diarrhea and abdominal discomfort. No significant changes were noted in the ECGs, vital signs and laboratory tests. At the 0.5 g b.i.d. dose, the bioavailability of T and TG was only slightly influenced by repeated administration. At the 1 g b.i.d. dose regimen, the extent of bioavailability of both T and TG was increased by 50-70%, indicating significant accumulation. Tmax was not significantly modified.
Conclusion: Oral administration of 0.5 g of nitazoxanide b.i.d. for 7 days with food in healthy volunteers is well-tolerated and is not associated with any significant accumulation of T or TG. A higher 1 g dose results in an increased frequency of gastrointestinal discomfort and is associated with significant accumulation of T and TG.