• Oscar A Linares, Jeffrey Fudin, Annemarie L Daly, and Raymond C Boston.
• *Translational Genomic Medicine Lab, Plymouth Pharmacokinetic Modeling Study Group, Plymouth, MI ∥Wayne State University Law School, Detroit, MI ¶Grace Hospice of Ann Arbor, Ann Arbor, MI †University of Connecticut School of Pharmacy, Storrs, CT ‡Western New England College of Pharmacy, Springfield, MA §Stratton VA Medical Center, Albany, NY #Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Kennett Square, PA.
• Clin J Pain. 2015 Dec 1; 31 (12): 1026-35.

Objectives(1) To quantify hydrocodone (HC) and hydromorphone (HM) metabolite pharmacokinetics with pharmacogenetics in CYP2D6 ultra-rapid metabolizer (UM), extensive metabolizer (EM), and poor metabolizer (PM) metabolizer phenotypes. (2) To develop an HC phenotype-specific dosing strategy for HC that accounts for HM production using clinical pharmacokinetics integrated with pharmacogenetics for patient safety.SettingIn silico clinical trial simulation.ParticipantsHealthy white men and women without comorbidities or history of opioid, or any other drug or nutraceutical use, age 26.3±5.7 years (mean±SD; range, 19 to 36 y) and weight 71.9±16.8 kg (range, 50 to 108 kg).Main Outcome MeasuresCYP2D6 phenotype-specific HC clinical pharmacokinetic parameter estimates and phenotype-specific percentages of HM formed from HC.ResultsPMs had lower indices of HC disposition compared with UMs and EMs. Clearance was reduced by nearly 60% and the t1/2 was increased by about 68% compared with EMs. The canonical order for HC clearance was UM>EM>PM. HC elimination mainly by the liver, represented by ke, was reduced about 70% in PM. However, HC's apparent Vd was not significantly different among UMs, EMs, and PM. The canonical order of predicted plasma HM concentrations was UM>EM>PM. For each of the CYP2D6 phenotypes, the mean predicted HM levels were within HM's therapeutic range, which indicates HC has significant phenotype-dependent pro-drug effects.ConclusionsOur results demonstrate that pharmacogenetics afford clinicians an opportunity to individualize HC dosing, while adding enhanced opportunity to account for its conversion to HM in the body.

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