Naldemedine (S-297995) is a peripherally acting μ-opioid receptor antagonist for the treatment of opioid-induced constipation, a common side effect of opioid therapy. We determined the safety, tolerability, and pharmacokinetic profiles of oral naldemedine in healthy volunteers in 2 randomized, double-blind, placebo-controlled, phase 1 studies. In the single ascending dose study, subjects received a single dose of naldemedine (0.1-100 mg; n = 42) or placebo (n = 14). In the multiple ascending dose study, subjects received once-daily naldemedine (3-30 mg; n = 27) or placebo (n = 9) for 10 days. On day 1 of the single ascending dose studies and day 10 of the multiple ascending dose studies, respectively, the maximum plasma concentration levels of naldemedine were 1.98 to 2510 ng/mL and 73.8 to 700 ng/mL, peaked at 0.5 hours and 0.5 to 0.75 hours, and the fraction excreted in urine was 15.9% to 20.5% and 19.7% to 19.1%. There were no major safety or tolerability concerns even at naldemedine doses 150 to 500 times the therapeutic dose of 0.2 mg. The incidence of adverse events was not dose dependent. Gastrointestinal adverse events occurred more frequently with naldemedine vs placebo, and all of these were considered treatment related. Overall, naldemedine was rapidly absorbed, and no safety or tolerability issues were noted at the doses evaluated.