CYP2D6 Pharmacogenetic and Oxycodone Pharmacokinetic Association Study in Pediatric Surgical Patients

Balyan, Rajiv; Mecoli, Marc; Venkatasubramanian, Raja; Chidambaran, Vidya; Kamos, Nichole; Clay, Smokey; Moore, David L.; Mavi, Jagroop; Glover, Chris D.; Szmuk, Peter; Vinks, Alexander A.; Sadhasivam, Senthilkumar

doi:10.2217/pgs-2016-0183

Cited by 42 publications

(23 citation statements)

References 39 publications

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“…All C max values of oxycodone were below 10 ng/mL, C max of oxymorphone was below 0.3 ng/mL, and t ½ of oxycodone was 2.7 h. Patients with a more active CYP2D6 phenotype (n = 13 or 16) had higher concentrations of oxymorphone in comparison with phenotypes with less activity of CYP2D6 (n = 17 or 14). However, oxymorphone C max and oxymorphone:oxycodone ratios were low, between 0.01 and 0.05, in all three phenotypes (PMs, IMs and NMs) [89].…”

Section: Oxycodone In Childrenmentioning

confidence: 85%

“…Balyan et al [89] evaluated the impact of genetic polymorphism of CYP2D6 on the PK of oxycodone in 30 children aged 2-17 years receiving oxycodone 0.07-0.1 mg/kg orally in the early postoperative period. Consistent with earlier data, delayed absorption was observed in some subjects, with a T max of 12 h indicating that absorption of swallowed oxycodone is erratic early after surgery and anaesthesia.…”

Section: Oxycodone In Childrenmentioning

confidence: 99%

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Updated Clinical Pharmacokinetics and Pharmacodynamics of Oxycodone

et al. 2019

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Global oxycodone consumption has increased sharply during the last two decades, and, in 2008, oxycodone consumption surpassed that of morphine. As oxycodone was synthesized in 1916 and taken to clinical use a year later, it has not undergone the same approval process required by today's standards. Most of the basic oxycodone pharmacokinetic (PK) data are from the 1990s and from academic research; however, a lot of additional data have been published over the last 10 years. In this review, we describe the latest oxycodone data on special populations, including neonates, children, pregnant and lactating women, and the elderly. A lot of important drug interaction data have been published that must also be taken into account when oxycodone is used concomitantly with cytochrome P450 (CYP) 3A inducers and inhibitors and/or CYP2D6 inhibitors. In addition, we gathered data on abuse-deterrent oxycodone formulations, and the PK of alternate administration routes, i.e. transmucosal and epidural, are also described. Mari Kinnunen and Panu Piirainen contributed equally to this work.

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Section: Oxycodone In Childrenmentioning

confidence: 85%

Section: Oxycodone In Childrenmentioning

confidence: 99%

Updated Clinical Pharmacokinetics and Pharmacodynamics of Oxycodone

et al. 2019

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“…Although differences in the pharmacokinetics of oxycodone based on CYP2D6 metabolizer status are evident, there are contradictory data regarding the differences in analgesia or toxicity (reviewed in [ 63 , 64 ]). There is one report of the impact of CYP2D6 metabolizer status on oxycodone pharmacokinetics in adolescents, where results were consistent with adult pharmacokinetic studies [ 18 ]. Although this study confirmed that CYP2D6 normal metabolizers had higher oxymorphone exposure than poor or intermediate metabolizers, more data are needed to support the oxycodone– CYP interaction before genotype-guided oxycodone dosing is clinically implemented for children.…”

Section: Resultsmentioning

confidence: 53%

Clinical Pharmacogenetics of Cytochrome P450-Associated Drugs in Children

Aka

Bernal

Carroll

et al. 2017

JPM

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Cytochrome P450 (CYP) enzymes are commonly involved in drug metabolism, and genetic variation in the genes encoding CYPs are associated with variable drug response. While genotype-guided therapy has been clinically implemented in adults, these associations are less well established for pediatric patients. In order to understand the frequency of pediatric exposures to drugs with known CYP interactions, we compiled all actionable drug–CYP interactions with a high level of evidence using Clinical Pharmacogenomic Implementation Consortium (CPIC) data and surveyed 10 years of electronic health records (EHR) data for the number of children exposed to CYP-associated drugs. Subsequently, we performed a focused literature review for drugs commonly used in pediatrics, defined as more than 5000 pediatric patients exposed in the decade-long EHR cohort. There were 48 drug–CYP interactions with a high level of evidence in the CPIC database. Of those, only 10 drugs were commonly used in children (ondansetron, oxycodone, codeine, omeprazole, lansoprazole, sertraline, amitriptyline, citalopram, escitalopram, and risperidone). For these drugs, reports of the drug–CYP interaction in cohorts including children were sparse. There are adequate data for implementation of genotype-guided therapy for children for three of the 10 commonly used drugs (codeine, omeprazole and lansoprazole). For the majority of commonly used drugs with known CYP interactions, more data are required to support pharmacogenomic implementation in children.

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“…One study of postsurgical paediatric patients found greater levels of oxymorphone in children who were RM or EM phenotypes compared with PM and IM phenotypes. 41 The clinical implications of this have not been adequately studied but it would seem that the RM and EM phenotypes would have less analgesia. 42 Tramadol, like codeine, is a prodrug that requires conversion to its active metabolite and thus also subject to variable metabolism; ultra-rapid metabolism has resulted in at least one fatality.…”

Section: Polymorphisms and Risk For Respiratory Depressionmentioning

confidence: 99%

Obstructive sleep apnoea and polymorphisms: implications for anaesthesia care

CotÃ

2020

South Afr J Anaesth Analg

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With a worldwide obesity pandemic, the incidence of obstructive sleep apnoea (OSA) is increasing; obesity is the most significant risk factor in children. Increasing evidence suggests that OSA is in part mediated through markers of inflammation. Systemic and pulmonary hypertension, right ventricular hypertrophy, prediabetes, and other conditions are common. Adenotonsillectomy improves only ~70% of children; 30% require other interventions, e.g. weight loss programs. The gold standard for diagnosis is a sleep-polysomnogram which are expensive and not readily available. The McGill oximetry score (saw-tooth desaturations during obstruction and arousal) is more cost-effective. Repeated episodes of desaturation alter the opioid receptors such that analgesia is achieved at much lower levels of opioid than in patients undergoing the same procedure but without OSA. This response is of great concern because a standard dose of opioids may be a relative overdose. Polymorphism variations in cytochrome CYP2D6 have major effects upon drug efficacy and side effects. Codeine, hydrocodone, oxycodone, and tramadol are all prodrugs that require CYP2D6 for conversion to the active compound. CYP2D6 is quite variable and patients can be divided into 4 classes: For codeine for example, poor metaboliser (PM) have virtually no conversion to morphine, intermediate metabolisers (IM) have some conversion to morphine, extensive metabolisers (EM) have a normal rate of conversion to morphine, and ultra-rapid metabolisers (RM) convert excessive amounts of codeine to morphine. Such variations result in some patients achieving no analgesia because there is reduced conversion to the active moiety whereas others convert an excessive amount of drug to the active compound thus resulting in relative or actual overdose despite appropriate dosing. Thus, OSA patients may have both opioid sensitivity due to recurrent desaturations and altered drug metabolism resulting in higher than intended blood levels of opioid. OSA patients should only receive one-third to half the usual dose of opioid. In those under the age of six, an effort should be made to avoid opioids altogether and use opioid sparing techniques such as alternating acetaminophen and ibuprofen.

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CYP2D6 Pharmacogenetic and Oxycodone Pharmacokinetic Association Study in Pediatric Surgical Patients

Abstract: 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.

Cited by 42 publications

References 39 publications

Updated Clinical Pharmacokinetics and Pharmacodynamics of Oxycodone

Updated Clinical Pharmacokinetics and Pharmacodynamics of Oxycodone

Clinical Pharmacogenetics of Cytochrome P450-Associated Drugs in Children

Obstructive sleep apnoea and polymorphisms: implications for anaesthesia care

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