title: Pharmacokinetic and pharmacodynamic modeling of opioid-induced gastrointestinal side effects in patients receiving tapentadol IR and oxycodone IR.
abstract: OBJECTIVE
  To understand the relationship between the risk of opioid-related gastrointestinal adverse effects (AEs) and exposure to tapentadol and oxycodone as well as its active metabolite, oxymorphone, using pharmacokinetic/pharmacodynamic models.
  
  
  METHODS
  The analysis was based on a study in patients with moderate-to-severe pain following bunionectomy. Population PK modeling was conducted to estimate population PK parameters for tapentadol, oxycodone, and oxymorphone. Time to AEs was analyzed using Cox proportional-hazards models.
  
  
  RESULTS
  Risk of nausea, vomiting, and constipation significantly increased with exposure to tapentadol or oxycodone/oxymorphone. However, elevated risk per drug exposure of AEs for tapentadol was ~3-4 times lower than that of oxycodone, while elevated AE risk per drug exposure of oxycodone was ~60 times lower than that for oxymorphone, consistent with reported in vitro receptor binding affinities for these compounds. Simulations show that AE incidence following administration of tapentadol IR is lower than that following oxycodone IR intake within the investigated range of analgesic noninferiority dose ratios.
  
  
  CONCLUSIONS
  This PK/PD analysis supports the clinical findings of reduced nausea, vomiting and constipation reported by patients treated with tapentadol, compared to patients treated with oxycodone.
authors.affiliation: Clinical Pharmacology, Advanced PK-PD Modeling and Simulation, Janssen Research and Development, Raritan, New Jersey, USA. sxu26@its.jnj.com
authors.forename: Xu Steven
authors.initials: XS
authors.lastname: Xu
authors.forename: Mila
authors.initials: M
authors.lastname: Etropolski
authors.forename: David
authors.initials: D
authors.lastname: Upmalis
authors.forename: Akiko
authors.initials: A
authors.lastname: Okamoto
authors.forename: Rachel
authors.initials: R
authors.lastname: Lin
authors.forename: Partha
authors.initials: P
authors.lastname: Nandy
mesh_terms: D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010098:Oxycodone / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D010636:Phenols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D016016:Proportional Hazards Models; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors; D000077432:Tapentadol
chemical_list: D010636:Phenols; D017450:Receptors, Opioid, mu; D010098:Oxycodone; D000077432:Tapentadol