Nitazoxanide pharmacokinetics and tolerability in man using single ascending oral doses.

OBJECTIVES: Nitazoxanide (N) is a new broad-spectrum intestinal antiparasitic agent. Deacetyl-N or tizoxanide (T) and its glucuronide (TG) are the major circulating species metabolites after oral administration of N. Bioavailability is substantially increased by food. The objectives of this phase IA study were to assess the tolerability and to determine the pharmacokinetic linearity of T and TG after single oral administration of increasing doses of N with and without food in healthy volunteer subjects. METHODS: Thirty-two healthy male volunteers were randomly assigned to 1 of 4 treatment groups. In each successive group, 2 subjects received a placebo and 6 received a single oral dose of 1 g, 2 g, 3 g, or 4 g of N, first under fasted conditions and a week later with a standardized breakfast. Blood samples were collected during 24 h for plasma determination of T and TG. General tolerability, adverse reactions, ECG, vital signs and laboratory tests were recorded. RESULTS: Tolerability was good up to the maximum dose of 4 g. Mild, mostly gastrointestinal side effects were observed and their frequency increased significantly with the dose level. No significant changes were noted in the ECGs, vital signs and laboratory tests. Plasma concentrations increased linearly with the dose from 1 - 4 g, although a trend to increased bioavailability was observed at 4 g. Food approximately doubled the concentrations of T and TG irrespective of dose. Peak times and apparent half-lives increased in proportion to the dose. The apparent body clearance for total T (T+TG) at the highest dose was only half that at the low dose. TG was eliminated more slowly than T. CONCLUSION: Nitazoxanide can be safely administered up to 4 g single oral doses, with or without food. The slow elimination of TG and the overproportional concentrations at the highest dose can be accounted for by solubility- or transport-limited elimination mechanisms becoming apparent at the upper dose level.

Nitazoxanide pharmacokinetics and tolerability in man during 7 days dosing with 0.5 g and 1 g b.i.d.

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.