Abstract
ABSTRACTPurposeTo characterize population pharmacokinetic (PK) of naldemedine, to identify factors which influence naldemedine PK, and to evaluate their clinical relevancy based on exposure-response relationships.MethodsA population PK model was developed with pooled naldemedine concentrations from healthy subjects, patients with chronic non-cancer pain and opioid-induced constipation (OIC), and cancer patients with OIC. Exposure-response analyses were performed with efficacy (responder or non-responder) and safety (occurrence of gastrointestinal disorders or not) data in phase 2b and phase 3 studies.ResultsNaldemedine plasma concentrations were adequately described by a 2-compartment model with first-order absorption and absorption lag time. The final model included the effects of age, creatinine clearance, race, and gender on apparent total clearance; the effects of body weight, health status, and food condition on apparent volume of central compartment; and the effect of age on first-order rate of absorption. When subjects took 0.2 mg of naldemedine once daily, the probability of spontaneous bowel movement (SBM) responders was predicted to be approximately 50%, while that of severe gastrointestinal disorders was predicted to be less than 3%. The influence of the covariates on PK was not considered clinically significant because similar efficacy and safety were expected based on the exposure-response analysis.ConclusionsThe covariates are identified in the population PK analysis; however, no dose-adjustment is required for them based on the exposure-response analysis.
Highlights
Naldemedine, an orally active peripherally-acting μ-opioid receptor antagonist (PAMORA), has been developed by Shionogi & Co., Ltd. (Shionogi) for treatment of opioidinduced constipation (OIC) in adult patients with pain who have been treated with opioids
The drug was first approved in March 2017 in the United States for the treatment of OIC in adult patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment, who do not require frequent opioid dosage escalation
Of the 9077 plasma naldemedine concentrations, 39 data items were excluded for the following reasons;[14] due to no measurement, 4 due to unidentified blood sampling time or unidentified dosing time, 2 due to detectable naldemedine concentration before the initial dose, and 19 due to their being unexpected outliers
Summary
Naldemedine, an orally active peripherally-acting μ-opioid receptor antagonist (PAMORA), has been developed by Shionogi & Co., Ltd. (Shionogi) for treatment of opioidinduced constipation (OIC) in adult patients with pain who have been treated with opioids. Naldemedine, an orally active peripherally-acting μ-opioid receptor antagonist (PAMORA), has been developed by Shionogi & Co., Ltd. The drug was first approved in March 2017 in the United States for the treatment of OIC in adult patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment, who do not require frequent (e.g., weekly) opioid dosage escalation. This drug was subsequently approved in Japan for the treatment of opioid-induced constipation in adult patients with cancer and non-cancer pain (8,9). The recommended dosage for adults is 0.2 mg once daily, taken with or without food (10)
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