Population Pharmacokinetics and Exposure-Response Relationships of Naldemedine.

Purpose: To characterize population pharmacokinetic (PK) of naldemedine, to identify factors which influence naldemedine PK, and to evaluate their clinical relevancy based on exposure-response relationships.

Methods: A 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.

Results: Naldemedine 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.

Conclusions: The covariates are identified in the population PK analysis; however, no dose-adjustment is required for them based on the exposure-response analysis.