Population Pharmacokinetics and Pharmacogenomics of Oral Oxycodone in Pediatric Surgical Patients
| Status: | Recruiting |
|---|---|
| Healthy: | No |
| Age Range: | Any - 6 |
| Updated: | 2/17/2019 |
| Start Date: | May 2014 |
| End Date: | December 2019 |
| Contact: | Christine Dube, MS, BSN, RN |
| Email: | Christine.Dube@childrens.harvard.edu |
| Phone: | 617-355-6185 |
Oxycodone is an oral opioid analgesic that is most commonly prescribed for the management of
pain in post-operative patients at Boston Children's Hospital. Oxycodone has been widely used
in adults and children to relieve post-operative pain. However, its pharmacokinetics (what it
does in the body) and pharmacodynamics (how it works) have not been well established in
children. Some children, because of their specific genetic make-up, may metabolize the drug
more quickly and therefore may be at risk for more side effects in the commonly prescribed
dose. We would like to find out more about how this drug is absorbed, metabolized and
excreted in children. In order to study these aspects, we would like to give oxycodone to
surgical patients at Boston Children's Hospital then measure its metabolic activity and also
perform a genetic analysis. The genetic testing is specifically to analyze the following
genotypes only: cytochrome P450 2D6 (CYP2D6) and cytochrome P450 3A4 (CYP3A4), which
represent the differences in cytochrome P450 metabolism of oxycodone.
pain in post-operative patients at Boston Children's Hospital. Oxycodone has been widely used
in adults and children to relieve post-operative pain. However, its pharmacokinetics (what it
does in the body) and pharmacodynamics (how it works) have not been well established in
children. Some children, because of their specific genetic make-up, may metabolize the drug
more quickly and therefore may be at risk for more side effects in the commonly prescribed
dose. We would like to find out more about how this drug is absorbed, metabolized and
excreted in children. In order to study these aspects, we would like to give oxycodone to
surgical patients at Boston Children's Hospital then measure its metabolic activity and also
perform a genetic analysis. The genetic testing is specifically to analyze the following
genotypes only: cytochrome P450 2D6 (CYP2D6) and cytochrome P450 3A4 (CYP3A4), which
represent the differences in cytochrome P450 metabolism of oxycodone.
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. [6] 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). Given that
BCH has switched (from codeine) to oxycodone as the most common opioid prescribed for all
postoperative patients and the recent concerns of serious side effects from codeine. It is
important to further investigate oral oxycodone to optimize dosing recommendations.
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. [6] 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). Given that
BCH has switched (from codeine) to oxycodone as the most common opioid prescribed for all
postoperative patients and the recent concerns of serious side effects from codeine. It is
important to further investigate oral oxycodone to optimize dosing recommendations.
Inclusion Criteria:
- A total of 68 generally healthy, opioid-naive children, aged 0-6 years, scheduled as
in-patient surgery for ventriculoperitoneal shunt placement/revision or Craniotomy
(Neurosurgery service), Cleft lip/palate repair (plastic surgery service) and
hypospadias repair or ureteral urethral reimplantation (genitourinary surgery service)
will be enrolled in the study.
Exclusion Criteria:
- Children will be excluded if they are currently taking any medications which are
CYP3A4 or CYP2D6 inhibitors/inducers or have a history of allergy or hypersensitivity
to oxycodone, have any condition that might interfere with GI absorption,
distribution, hepatic metabolism or renal excretion of r oxycodone, or a diagnosis of
sleep apnea or impaired respiratory reserve.
We found this trial at
1
site
Boston, Massachusetts 02115
Principal Investigator: Patcharee Sriswasdi, MD
Phone: 617-355-6185
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