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ABSTRACT: 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.
SUBMITTER: Kubota R
PROVIDER: S-EPMC6182381 | biostudies-literature | 2018 Oct
REPOSITORIES: biostudies-literature
Kubota Ryuji R Fukumura Kazuya K Wajima Toshihiro T
Pharmaceutical research 20181002 11
<h4>Purpose</h4>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.<h4>Methods</h4>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 (responde ...[more]