Nitazoxanide pharmacokinetics and tolerability in man using single ascending oral doses

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.

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.

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.

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.