Phase 1, Randomized, Double‐Blind, Placebo‐Controlled Studies on the Safety, Tolerability, and Pharmacokinetics of Naldemedine in Healthy Volunteers

Naldemedine(S-297995) is a peripherally acting μ-opioid receptorantagonist for the treatment of opioid-induced constipation, a common side effect of opioid therapy. We determined the safety, tolerability, and pharmacokinetic profiles of oral naldemedinein healthy volunteers in 2 randomized, double-blind, placebo-controlled, phase 1 studies. In the single ascendingdose study, subjects received a single dose of naldemedine(0.1-100 mg; n = 42) or placebo (n = 14). In the multiple ascendingdose study, subjects received once-daily naldemedine(3-30 mg; n = 27) or placebo (n = 9) for 10 days. On day 1 of the single ascendingdose studies and day 10 of the multiple ascendingdose studies, respectively, the maximum plasma concentration levels of naldemedinewere 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 naldemedinedoses 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 naldemedinevs placebo, and all of these were considered treatment related. Overall, naldemedinewas rapidly absorbed, and no safety or tolerability issues were noted at the doses evaluated.