title: Personalized oxycodone dosing: using pharmacogenetic testing and clinical pharmacokinetics to reduce toxicity risk and increase effectiveness.
abstract: OBJECTIVE
  To develop a framework for integrating pharmacogenetics with clinical pharmacokinetics for personalized oxycodone dosing based on a patient's CYP2D6 phenotype.
  
  
  METHODS
  Randomized, crossover, double-blind, placebo-controlled. Subjects were genotyped as CYP2D6 ultra-rapid metabolizer, extensive metabolizer, or poor metabolizer phenotypes. Five subjects from each phenotype were randomly selected for inclusion in our study.
  
  
  METHODS
  Studies were performed in silico.
  
  
  METHODS
  The subjects were male, age 26 years, height 181.2 cm, and weight 76.3 kg. They were healthy without comorbidities, and their medical examinations were normal.
  
  
  METHODS
  The trajectories of phenotype-specific plasma oxycodone concentration-time profiles were analyzed using weighted nonlinear least-squares regression with WinSAAM software. A global two-stage population-based model data analysis procedure was used to analyze the studies. Clinical pharmacokinetics were calculated using the R package cpk, eliminating the need to perform hand-calculations.
  
  
  RESULTS
  Our study shows how clinicians can reduce risk and increase effectiveness for oxycodone dosing by (1) determining the patient's likely metabolic response through testing a patient's CYP2D6 phenotype, and (2) calculating clinical pharmacokinetics specific to the patient's CYP2D6 phenotype to design a personalized oxycodone dosing regimen.
  
  
  CONCLUSIONS
  Personalized oxycodone dosing is a new tool for a clinician treating chronic pain patients requiring oxycodone. By expressing a patient's CYP2D6 phenotype pharmacokinetically, a clinician (at least theoretically) can improve the safety and efficacy of oxycodone and decrease the risk for iatrogenically induced overdose or death. Pharmacokinomics provides a general framework for the integration of pharmacogenetics with clinical pharmacokinetics into clinical practice for gene-based prescribing.
authors: Plymouth Pharmacokinetic Modeling Study Group, Plymouth, Michigan, USA.
authors: Oscar A
authors: OA
authors: Linares
authors: David
authors: D
authors: Daly
authors: Annemarie Daly
authors: AD
authors: Linares
authors: Darko
authors: D
authors: Stefanovski
authors: Raymond C
authors: RC
authors: Boston
mesh_terms: D000328:Adult; D000465:Algorithms; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D059350:Chronic Pain / Q000188:drug therapy* / Q000235:genetics; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D004311:Double-Blind Method; D005838:Genotype; D006801:Humans; D008297:Male; D008954:Models, Biological; D017711:Nonlinear Dynamics; D010098:Oxycodone / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D010149:Postoperative Pain / Q000188:drug therapy / Q000235:genetics; D010597:Pharmacogenetics / Q000379:methods*; D010641:Phenotype; D057285:Precision Medicine / Q000379:methods*; D012306:Risk
chemical_list: D000701:Analgesics, Opioid; D010098:Oxycodone; D019389:Cytochrome P-450 CYP2D6
keywords: CYP2D6; Clinical Pharmacokinetics; Clinical Pharmacology; Mathematical Medicine; Metabolism; Oxycodone; Pharmacogenetics; Pharmacogenomics; Pharmacokinomics