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Clinical Trial
. 2017 Mar;18(4):337-348.
doi: 10.2217/pgs-2016-0183. Epub 2017 Feb 17.

CYP2D6 pharmacogenetic and oxycodone pharmacokinetic association study in pediatric surgical patients

Rajiv Balyan  1   2 , Marc Mecoli  1   3 , Raja Venkatasubramanian  1   2 , Vidya Chidambaran  1   3 , Nichole Kamos  3 , Smokey Clay  1   3 , David L Moore  1   3 , Jagroop Mavi  1   3 , Chris D Glover  4 , Peter Szmuk  5   6 , Alexander Vinks  2   3 , Senthilkumar Sadhasivam  1   3
Affiliations
Clinical Trial

CYP2D6 pharmacogenetic and oxycodone pharmacokinetic association study in pediatric surgical patients

Rajiv Balyan et al. Pharmacogenomics. 2017 Mar.

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 Cmax, p = 0.016 for AUC0-6 and p = 0.026 for AUC0-24). 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 Cmax, p = 0.001 for AUC0-6 and p = 0.004 for AUC0-24).

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.

Keywords: CYP2D6; oxycodone; pediatrics; pharmacogenetics; pharmacokinetics; surgical pain.

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Conflict of interest statement

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.

Figures

<b>Figure 1.</b>
Figure 1.. Oxycodone metabolism mediated by CYP3A4 and CYP2D6.
Majority of circulatingoxycodone (∼80%) is N-demethylated to inactive metabolite noroxycodone by CYP3A4, while a minor portion is O-demethylated to active metabolite oxymorphone by CYP2D6. Both noroxycodone and oxymorphone are further metabolized to didemethylated metabolite noroxymorphone (a weak analgesic) by activity of CYP2D6 and CYP3A4 respectively.
<b>Figure 2.</b>
Figure 2.. Concentration–time profiles of oxycodone (A) and its active metabolite oxymorphone (B) in plasma of pediatric patients (n = 30).
Oxycodone was administered orally to children postoperatively; dosing was based on age (0.1 mg/kg for children ages 2–6 years, 0.08 mg/kg for ages 7–12 years, and 0.07 mg/kg for ages 13 –17 years). The blood samples were collected till 24 hours.
<b>Figure 3.</b>
Figure 3.. Comparison of Cmax of oxycodone and oxymorphone with oxycodone metabolism phenotype.
(A) Dose normalized maximum plasma concentration values of oxycodone in oxymorphone were compared in CYP2D6 phenotype groups PM/IM (n = 14) and EM (n = 16). The results are expressed as mean ± 95% CI. No statistical difference was observed in two groups in oxycodone Cmax values. The two groups were statistically significant in oxymorphone Cmax as determined by unpaired Mann–Whitney test. (B) Oxycodone and oxymorphone Cmax values were plotted with respect to CYP2D6 total activity score (TAS). A trend line was drawn connecting mean Cmax of groups with TAS values 1 and 2. The trend line showed higher slope for oxymorphone with high TAS associated with bigger Cmax. EM: Extensive metabolizer; IM: Intermediate metabolizer; PM: Poor metabolizer.
<b>Figure 4.</b>
Figure 4.. Comparison of oxycodone and oxymorphone AUC0–6 of with oxycodone metabolism phenotype.
(A) Dose normalized integrated exposure of oxycodone and oxymorphone were compared in CYP2D6 phenotype groups PM/IM (n = 14) and EM (n = 16). The results are expressed as mean ± 95% CI. No statistical difference was observed in two groups in oxycodone AUC0–6. A statistically significant difference in oxymorphone AUC0–6 was observed by unpaired Mann–Whitney test. (B) Oxycodone and oxymorphone AUC0–6 were plotted with respect to CYP2D6 total activity score (TAS). A trend line was drawn connecting mean AUC­0–6 of groups with TAS values 1 and 2. The trend line showed higher slope for oxymorphone with high TAS value associated with higher AUC­0–6. AUC: Area under the curve; EM: Extensive metabolizer; IM: Intermediate metabolizer; PM: Poor metabolizer.
<b>Figure 5.</b>
Figure 5.. Comparison of oxycodone and oxymorphone AUC0–24 of with oxycodone metabolism phenotype.
(A) Dose normalized integrated exposure of oxycodone and oxymorphone were compared in CYP2D6 phenotype groups PM/IM (n = 14) and EM (n = 16). The results are expressed as mean ± 95% CI. No statistical difference was observed in two groups in oxycodone AUC0–24. A statistically significant difference in oxymorphone AUC0–24 was observed by unpaired Mann–Whitney test. (B) Oxycodone and oxymorphone AUC0–24 were plotted with respect to CYP2D6 total activity score (TAS). A trend line was drawn connecting mean AUC­0–24 of groups with TAS values 1 and 2. The trend line showed higher slope for oxymorphone with high TAS value associated with higher AUC­0–24. AUC: Area under the curve; EM: Extensive metabolizer; IM: Intermediate metabolizer; PM: Poor metabolizer.
<b>Figure 6.</b>
Figure 6.. Comparison of oxycodone and oxymorphone Cmax ratio with oxycodone metabolism phenotype.
(A) The C­max ratio of oxymorphone/oxycodone for individual patient were compared based on their CYP2D6 phenotype groups PM/IM (n = 14) and EM (n = 16). The results are expressed as mean ± 95% CI. The Cmax ratios were higher in EM patients compared to PM/IM patients as calculated by unpaired Mann–Whitney test. (B) The oxymorphone and oxycodone Cmax ratios were plotted with respect to CYP2D6 total activity score (TAS). A trend line was drawn connecting mean Cmax ratios of groups with TAS values 1 and 2. The trend line showed high TAS value associated with higher Cmax ratio. EM: Extensive metabolizer; IM: Intermediate metabolizer; PM: Poor metabolizer.
<b>Figure 7.</b>
Figure 7.. Comparison of oxycodone and oxymorphone AUC0–6 ratio with oxycodone metabolism phenotype.
(A) The AUC0–6 ratio of oxymorphone/oxycodone for individual patient were compared based on their CYP2D6 phenotype groups PM/IM (n = 14) and EM (n = 16). The results are expressed as mean ± 95% CI. The AUC0–6 ratios were higher in EM patients compared to PM/IM patients as calculated by unpaired Mann–Whitney test. (B) The oxymorphone and oxycodone AUC0–6 ratios were plotted with respect to CYP2D6 total activity score (TAS). A trend line was drawn connecting mean AUC0–6 ratios of groups with TAS values 1 and 2. The trend line showed high TAS value associated with higher AUC0–6 ratio. AUC: Area under the curve; EM: Extensive metabolizer; IM: Intermediate metabolizer; PM: Poor metabolizer.
<b>Figure 8.</b>
Figure 8.. Comparison of oxycodone and oxymorphone AUC0–24 ratio with oxycodone metabolism phenotype.
(A) The AUC0–24 ratio of oxymorphone/oxycodone for individual patient were compared based on their CYP2D6 phenotype groups PM/IM (n = 14) and EM (n = 16). The results are expressed as mean ± 95% CI. The AUC0–24 ratios were higher in EM patients compared to PM/IM patients as calculated by unpaired Mann–Whitney test. (B) The oxymorphone and oxycodone AUC0–24 ratios were plotted with respect to CYP2D6 total activity score (TAS). A trend line was drawn connecting mean AUC0–24 ratios of groups with TAS values 1 and 2. The trend line showed high TAS value associated with higher AUC0–24 ratio. AUC: Area under the curve; EM: Extensive metabolizer; IM: Intermediate metabolizer; PM: Poor metabolizer.
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