title: Effects of aprepitant on the pharmacokinetics of controlled-release oral oxycodone in cancer patients.
abstract: OBJECTIVE
  Oxycodone is a µ-opioid receptor agonist widely used in the treatment of cancer pain. The predominant metabolic pathway of oxycodone is CYP3A4-mediated N-demethylation to noroxycodone, while a minor proportion undergoes 3-O-demethylation to oxymorphone by CYP2D6. The aim of this study was to investigate the effects of the mild CYP3A4 inhibitor aprepitant on the pharmacokinetics of orally administered controlled-release (CR) oxycodone.
  
  
  METHODS
  This study design was an open-label, single-sequence with two phases in cancer patients with pain who continued to be administered orally with multiple doses of CR oxycodone every 8 or 12 hours. Plasma concentration of oxycodone and its metabolites were measured up to 8 hours after administration as follows: on day 1, CR oxycodone was administered alone; on day 2, CR oxycodone was administered with aprepitant (125 mg, at the same time of oxycodone dosing in the morning). The steady-state trough concentrations (Css) were measured from day 1 to day 3.
  
  
  RESULTS
  Aprepitant increased the area under the plasma concentration-time curve (AUC0-8) of oxycodone by 25% (p<0.001) and of oxymorphone by 34% (p<0.001), as well as decreased the AUC0-8 of noroxycodone by 14% (p<0.001). Moreover, aprepitant increased Css of oxycodone by 57% (p = 0.001) and of oxymorphone by 36% (p<0.001) and decreased Css of noroxycodone by 24% (p = 0.02) at day 3 compared to day 1.
  
  
  CONCLUSIONS
  The clinical use of aprepitant in patients receiving multiple doses of CR oxycodone for cancer pain significantly altered plasma concentration levels, but would not appear to need modification of the CR oxycodone dose.
  
  
  BACKGROUND
  UMIN.ac.jp UMIN000003580.
authors.affiliation: Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Investigational Cancer Therapeutics, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center Hospital, Chiba, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Toyoda
authors.affiliation: Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Chayahara
authors.affiliation: Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Kiyota
authors.affiliation: Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Shimada
authors.affiliation: Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Imamura
authors.affiliation: Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe, Japan; Cancer Center, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Mukohara
authors.affiliation: Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe, Japan; Cancer Center, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Minami
mesh_terms: D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077608:Aprepitant; D019540:Area Under Curve; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009019:Morphinans / Q000097:blood; D009025:Morpholines / Q000494:pharmacology*; D009369:Neoplasms / Q000097:blood*; D010098:Oxycodone / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010111:Oxymorphone / Q000097:blood; D010146:Pain / Q000188:drug therapy
chemical_list: D000701:Analgesics, Opioid; D003692:Delayed-Action Preparations; D009019:Morphinans; D009025:Morpholines; D000077608:Aprepitant; C077256:noroxycodone; D010111:Oxymorphone; D010098:Oxycodone