A First-in-Human, Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple-Ascending Oral Dose Study To Assess the Safety and Tolerability of LFF571 in Healthy Volunteers

Abstract

Clostridium difficile is the leading cause of hospital-acquired infectious diarrhea. LFF571 is a novel inhibitor of the prokaryotic translation elongation factor Tu and is active against a range of bacterial species, including C. difficile. This first-in-human study investigated the safety and pharmacokinetics of single and multiple ascending oral doses of LFF571 in healthy subjects. This was a randomized, double-blind, placebo-controlled study. Except for one cohort, LFF571 was given with a high-fat meal to all single-dose cohorts (25 mg, 100 mg, 400 mg, and 1,000 mg). In the multiple-dose cohorts (25 mg, 100 mg, or 200 mg every 6 h for 10 days), LFF571 was given without regard to food. A total of 56 subjects completed the study, with 32 and 25 receiving single and multiple doses, respectively. There were no deaths, no serious adverse events, and no subject withdrawals due to an adverse event. The most common adverse event was diarrhea; gastrointestinal pain or distension was also noted. Diarrhea did not develop more frequently among subjects who received LFF571 than among those who received a placebo. LFF571 had limited systemic exposure and high steady-state fecal concentrations. The highest concentration of LFF571 in serum (3.2 ng/ml) was observed after the last dose in a subject who received 200 mg every 6 h for 10 days. LFF571 was generally safe and well tolerated in single and multiple oral doses in healthy subjects. The minimal serum and high fecal concentrations support the further development of LFF571 for the treatment of C. difficile infections.