Browsing by Author "O'Kane, Aislinn"

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    A systematic review of dexmedetomidine pharmacology in pediatric patients
    (Wiley, 2024) O'Kane, Aislinn; Quinney, Sara K.; Kinney, Emily; Bergstrom, Richard F.; Tillman, Emma M.; Medicine, School of Medicine
    Dexmedetomidine is a centrally acting alpha-2 agonist used for initiation and maintenance of procedural sedation and mechanical ventilation in adult and pediatric settings. It is commonly used in both pediatric and neonatal intensive care units. Dexmedetomidine requires extensive titration, and patients can be over or under-sedated during titration, leading to adverse events such as hypotension and bradycardia, or inadequate sedation, which can result in self-extubation. There is a critical need to identify factors that contribute to variation in metabolism, clearance, and downstream targets of dexmedetomidine so that individualized pediatric dosing regimens can be developed. This review is focused on dexmedetomidine pharmacokinetics and pharmacodynamics in the pediatric population and dexmedetomidine-related pharmacogenes in both adults and children. We found that the strongest predictors of dexmedetomidine pharmacokinetics were age and size. Multiple pharmacogenes of significance have been identified, including ADRA2A, UGT2B10, UGT1A4, CYP1A2, CYP2A6, and CYP2D6. Evidence is weak for the correlation of these individual polymorphic genes with dexmedetomidine pharmacokinetics/dynamics, though there may be a polygenetic influence on pharmacologic response. This review provides a comprehensive overview of the genomic data gathered to date. We aim to summarize current pharmacologic studies regarding dexmedetomidine use and pharmacology in pediatric patients.
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    Population Pharmacokinetics and Transfer of Gabapentin When Used as a Pain Adjunct for Cesarean Deliveries
    (Wiley, 2025) Silvola, Rebecca; O'Kane, Aislinn; Heathman, Michael; Marotta, Hannah; Trussel, Hayley; Ray, Bobbie; Dowden, Shelley; Masters, Andrea R.; Haas, David M.; Quinney, Sara K.; Medicine, School of Medicine
    Enhanced Recovery After Surgery (ERAS) protocols for cesarean deliveries (CDs) utilize multimodal pain management strategies that often include gabapentin. While gabapentin is excreted in breast milk, its pharmacokinetics in immediately postpartum lactating women are not known. This observational pharmacokinetic study (NCT05099484) enrolled 21 healthy singleton pregnant individuals, ≥ 18 years old, undergoing CD and planning to breastfeed. Participants received 300 mg oral gabapentin before CD and every 6 h for 48 h per hospital protocol. Serial maternal plasma and breast milk samples were collected over a single dosing interval. Gabapentin pharmacokinetics were assessed using two structurally distinct population pharmacokinetic (POPPK) models to describe transfer of drug into breast milk utilizing (A) milk-to-plasma ratio and (B) inter-compartmental rate constants. These models were then used to estimate exposure to breastfed infants. Postpartum gabapentin plasma concentrations fit a 1-compartment model that was adapted to include breast milk concentrations. The two POPPK models both estimated relative infant doses (RID0-48h) of gabapentin < 0.15% of maternal dose within the first 48 h postpartum. Infant daily dose (IDD) from 24 to 48 h was estimated to be 0.0137 (0.0058-0.0316) mg/kg/day and 0.0139 (0.00041-0.0469) mg/kg/day by models A and B, respectively. These findings indicate limited neonatal exposure to gabapentin administered as part of a postpartum enhanced recovery after surgery protocol.
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    UGT2B10 Variant Effects on Dexmedetomidine Metabolism Using Nicotine Studies
    (2025-04-25) Hardin, Cassidy; O'Kane, Aislinn; Quinney, Sara
    Background: Dexmedetomidine is a procedural sedative primarily metabolized by the UDP-glucuronosyltransferase (UGT) 2B10. UGT2B10 also contributes to nicotine metabolism. Most research on the effect of gene variants on UGT2B10’s glucuronidation efficacy has focused on nicotine. This study outlines current data on the relationship between UGT2B10 pharmacogenomics, nicotine pharmacokinetics, and race, then extrapolates that information to dexmedetomidine. Methods: A literature review was conducted on UGT2B10 variants and dexmedetomidine or nicotine in PubMed. Due to lack of studies on dexmedetomidine glucuronidation, studies using nicotine were used to classify variants as poor, intermediate, or extensive metabolizers; characterize their expression in African/African Americans (AA) and Europeans (C), and establish their respective activity based on nicotine metabolite percentages. Results: UGT2B10 accounts for about 20% of nicotine metabolism. The UGT2B10 variants rs61750900 (AA= 37.62%; C=0.18%) and rs2942857 (AA=4.42%; C=9.28%) are nonfunctional. Poor metabolizers (PM) are homozygous for one of these variants and see a 97% decrease in UGT2B10 metabolites. Intermediate metabolizers (IM) have one variant allele and one wild-type allele, with a 32% decrease in UGT2B10 metabolites. Extensive metabolizers (EM), have two wild-type alleles. Metabolites from other pathways increase as UGT2B10 metabolites decrease. These results were superimposed onto dexmedetomidine metabolism to predict metabolite percentages in UGT2B10 IM and PM. In PM, only 1.02% of dexmedetomidine metabolites were predicted to be from UGT2B10. Conclusion: Nicotine metabolism data suggests variants of UGT2B10 significantly impact dexmedetomidine metabolism. PMs have 97% decreased nicotine UGT2B10 metabolism and a compensatory increase in nicotine’s other metabolites. UGT2B10 accounts for the largest portion of dexmedetomidine metabolism. Thus, UGT2B10 PMs may have decreased glucuronide metabolites, with increased proportion of other pathways. Giving the same dose of dexmedetomidine to PM or ultrarapid metabolizers (UM) may result in toxicity or undersedation, respectively. More research needs to be done on UGT2B10 variants to optimize patient care.