Research Article

CYP2D6 pharmacogenetic and oxycodone pharmacokinetic association study in pediatric surgical patients

Department of Anesthesia, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 2001, Cincinnati, OH 45229, USA

Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA

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Marc Mecoli

Department of Anesthesia, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 2001, Cincinnati, OH 45229, USA

Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA

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Raja Venkatasubramanian

Department of Anesthesia, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 2001, Cincinnati, OH 45229, USA

Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA

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Vidya Chidambaran

Department of Anesthesia, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 2001, Cincinnati, OH 45229, USA

Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA

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Nichole Kamos

Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA

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Smokey Clay

Department of Anesthesia, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 2001, Cincinnati, OH 45229, USA

Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA

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David L Moore

Department of Anesthesia, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 2001, Cincinnati, OH 45229, USA

Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA

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Jagroop Mavi

Department of Anesthesia, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 2001, Cincinnati, OH 45229, USA

Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA

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Chris D Glover

Department of Anesthesia, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA

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Peter Szmuk

Department of Anesthesiology & Pain Management, University of Texas Southwestern & Children's Medical Center, Dallas, TX 75390, USA

Outcome Research Consortium, Cleveland, OH 44195, USA

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Alexander Vinks

Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA

Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA

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Senthilkumar Sadhasivam

*Author for correspondence:

E-mail Address: senthilkumar.sadhasivam@cchmc.org

Department of Anesthesia, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 2001, Cincinnati, OH 45229, USA

Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA

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Published Online:17 Feb 2017https://doi.org/10.2217/pgs-2016-0183

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Abstract

Aim: Oxycodone is partly metabolized to the active metabolite oxymorphone by hepatic CYP2D6 in the liver. Significant genetic variability in CYP2D6 activity affects oxymorphone formation. This study aimed to associate CYP2D6 genotype and oxycodone's metabolism. Methods: 30 children were administered oral oxycodone postoperatively. Plasma levels of oxycodone and oxymorphone, and CYP2D6 genotype were analyzed. CYP2D6 genotype and oxycodone metabolism phenotype were determined based on CYP2D6 total activity score (TAS) and metabolism phenotype: poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM) or ultrarapid metabolizer (UM). Results: Compared with PM/IM subjects, significantly greater oxymorphone exposure was seen in EM subjects (p = 0.02 for C_max, p = 0.016 for AUC_0–6 and p = 0.026 for AUC_0–24). Similarly, higher TAS value was found to be associated with greater oxymorphone exposure. Higher conversion of oxycodone to oxymorphone was observed in EM subjects compared with PM/IM subjects (p = 0.0007 for C_max, p = 0.001 for AUC_0–6 and p = 0.004 for AUC_0–24). Conclusion:CYP2D6 phenotypes explain metabolism of oxycodone in children, and oxymorphone exposure is higher in CYP2D6 EM phenotype. Further studies are needed to predict the occurrence of adverse event and tailor oxycodone dose for a specific CYP2D6 phenotype.

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References

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Vol. 18, No. 4

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History

Published online 17 February 2017

Published in print March 2017

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Author contributions

The authors directed and had access to all the analyses and the full clinical and genetic database, wrote all drafts of the report, decided to publish the results, and attest for the accuracy and completeness of the data. S Sadhasivam participated in design, funding conduct and supervision of the project. All authors contributed to subject recruitment, data analysis and made critical revisions to the report for important intellectual content.

Financial & competing interests disclosure

The project's pharmacokinetic assay was supported by Vistapharm as part of an ongoing Phase IV study to characterize the pharmacokinetics and to evaluate the safety of oxycodone in children (Principal Investigator: S Sadhasivam). In addition, the CYP2D6 genetic analysis and data analysis were partly supported by funds from Cincinnati Children's Hospital Medical Center and the R01 HD089458 through the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH (Principal Investigator: S Sadhasivam). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

All authors declare that approval was obtained from Institutional Review Board (IRB) and principles outlined in Declaration of Helsinki were followed in performing this study. Informed consent was obtained from participants in study involving human subjects.

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