title: Modelling the PKPD of oxycodone in experimental pain - Impact of opioid receptor polymorphisms.
abstract: BACKGROUND
  Polymorphisms in the opioid receptor genes may affect the pharmacodynamics (PD) of oxycodone and be part of the reason behind the diversity in clinical response. The aim of the analysis was to model the exposure-response profile of oxycodone for three different pain variables and search for genetic covariates. Model simulations were used to predict how population and effect-size impact the power to detect clinical significant SNPs.
  
  
  METHODS
  The population pharmacokinetic-pharmacodynamic (PKPD) model of oral single-dosed oxycodone was based on pooled data from three published studies in healthy volunteers. Pain tolerance data from muscle pressure (n=36), visceral pressure (n=54) and skin pinch (n=34) were included. Genetic associations with 18 opioid-receptor SNPs were explored using a stepwise covariate approach. Model simulations were performed using the estimated model parameters.
  
  
  RESULTS
  None of the selected SNPs were associated with analgesic response of oxycodone at P<0.001. Baseline response in muscle cuff pressure was associated with OPRK1 rs7016778 and rs7824175 (P<0.001). Simulations indicated that large differences in drug response between genotypes (>50% for similar population sizes) or large populations (n>200 for a 20% response difference) are necessary to identify clinical significant SNP effects due to high population variability.
  
  
  CONCLUSIONS
  A population PKPD model has been developed for oral oxycodone using three different pain variables to explore impact of genetic covariates and study design. None of the selected polymorphisms were significantly associated with analgesic response of oxycodone, but an association of baseline response in muscle cuff pressure with two OPRK1 SNPs was identified.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Olsen
authors.affiliation: Australian Centre for Pharmacometrics, School of Pharmacy and Medical Sciences, City East Campus, North Terrace, University of South Australia, Adelaide SA 5000, Australia.
authors.forename: David J R
authors.initials: DJ
authors.lastname: Foster
authors.affiliation: Australian Centre for Pharmacometrics, School of Pharmacy and Medical Sciences, City East Campus, North Terrace, University of South Australia, Adelaide SA 5000, Australia.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Upton
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark; Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Mølleparkvej 4, DK-9000 Aalborg, Denmark.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Olesen
authors.affiliation: Royal Marsden and Royal Brompton Palliative Care Service, Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK; Molecular Genetics & Genomics, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
authors.forename: Joy R
authors.initials: JR
authors.lastname: Ross
authors.affiliation: Royal Marsden and Royal Brompton Palliative Care Service, Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK; Molecular Genetics & Genomics, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Droney
authors.affiliation: Molecular Genetics & Genomics, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
authors.forename: Hiroe
authors.initials: H
authors.lastname: Sato
authors.affiliation: Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Mølleparkvej 4, DK-9000 Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Sdr. Skovvej 11, DK-9000 Aalborg, Denmark.
authors.forename: Asbjørn M
authors.initials: AM
authors.lastname: Drewes
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark. Electronic address: mdkd@novonordisk.com.
authors.forename: Mads
authors.initials: M
authors.lastname: Kreilgaard
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000701:Analgesics, Opioid / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010098:Oxycodone / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011957:Receptors, Opioid / Q000235:genetics*; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D011957:Receptors, Opioid; D010098:Oxycodone
keywords: Analgesia; Experimental pain; Opioid receptor genes; Oxycodone; PKPD; Population