Population Pharmacokinetics and Pharmacogenomics of Oral Oxycodone in Thai Pediatric Surgical Patients

Oxycodone is the most commonly used analgesic for the management of moderate and severe postoperative pain. The efficacy of Oxycodone as a potent opioid has been confirmed in children. The principal metabolic pathway of oxycodone in humans is N-demethylation via enzyme CYP3A4 to generate inactive noroxycodone. A smaller amount (approximately 11%) is O-demethylated by cytochrome P450 enzyme CYP2D6 to become oxymorphone, the active and potent metabolite which exhibits about 40 times the affinity and 8 times the potency on μ-opioid receptors compared to the mother substance. Approximate frequencies of cytochrome P450 enzyme CYP2D6 phenotypes for the Caucasian population are: poor metabolizers 5 - 10%, extensive/intermediate metabolizers 65-90%, and ultra-rapid metabolizers 5 - 10%. Kirchheiner and colleagues noticed more codeine-related sedative side-effects in ultra-rapid metabolizers. In studies investigating extensive and poor metabolizers, codeine side-effects do not seem to be related to CYP2D6 genotype. However, clinical investigations of CYP2D6 genotype in the postoperative pain setting have shown conflicting results, and well-designed prospective studies are lacking. Taken together, these results demonstrate the need for careful pharmacokinetic studies in children who received a pharmacologic agent, such as oxycodone, which is metabolized by the enzyme CYP2D6. The population PK of oxycodone and its metabolites has not been fully established for oral oxycodone in pediatric patients. In addition, there is a group of ultra-rapid metabolizers (approximately 4.5% of the population, but as high as 20% in some particular ethnic groups; East African and Saudi Arabian populations) which may be at risk for serious side effects in the commonly prescribed dose (which is extrapolated from adult recommendations). It is important to further investigate oral oxycodone to optimize dosing recommendations.