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. Design: 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. Setting: Studies were performed in silico. Subjects: The subjects were male, age 26 years, height 181.2cm, and weight 76.3kg. 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. © 2014 American Academy of Pain Medicine.