PWIII-004 - EFFECT OF CYP3A AND CYP2D6 GENOTYPES ON THE PHARMACOKINETICS OF OXYCODONE IN CHILDREN.

B. Arul Dhas^1,2, S. Quinney¹, B. Overholser^1,3, M. Heathman¹, S. Sadhasivam^1,4; ¹Indiana University, Indianapolis, IN, USA, ²Christian Medical College, Vellore, Tamil Nadu, India, ³Purdue University College of Pharmacy, West Lafayette, Indiana, USA, ⁴University of Pittsburgh, Pittsburgh, PA, USA.

Background: Oxycodone’s high pharmacokinetic (PK) variability is generally attributed to the polymorphisms in CYP450 enzymes. We studied the effect of CYP2D6 and CYP3A4/5 genotypes on the PK of oxycodone in children undergoing major surgeries.

Methods: Children undergoing surgery for idiopathic scoliosis or pectus excavatum were enrolled in an observational PK study (IRB# 1707525204). Oral oxycodone (2.5 - 5 mg) was given every 6 hours postoperatively. Blood samples (5–8) were collected across 3 interdose intervals. Star alleles of CYP enzymes and a few other selected intronic SNPs were derived from the allelic information obtained by whole-genome sequencing. PK modeling was performed using NONMEM 7.4 using SAEM. A stepwise covariate approach with a forward selection (p = 0.05) and backward elimination (p = 0.01) was used. The predictive performance and robustness of the models were evaluated using prediction-corrected visual predictive checks (VPC) and bootstrapping.

Results: 89 children (median 14, IQR 13-15 years) were recruited. PK data were best described by a one‐compartment model for oxycodone, noroxycodone, and noroxymorphone with interindividual variability on the volume of distribution of the drug and formation clearances of each metabolite. The absorption phase was well‐described by a first‐order process. Oral bioavailability was fixed to 1. Formation clearance of noroxycodone decreased by 0.73-fold with heterozygous CYP3A4. Formation clearance of noroxymorphone increased 1.19-fold with every unit increase in CYP2D6 activity score. The VPC and the bootstrap results were within acceptable limits.

Conclusion: A PK model of oxycodone and metabolites in children indicates that CYP3A4 and CYP2D6 pharmacogenomics are associated with the formation of noroxycodone and noroxymorphone, respectively.