Influence of novel CYP2C-haplotype on proton pump inhibitor pharmacokinetics in children.

In this brief report, we provide an analysis of the influence of a novel CYP2C haplotype (CYP2C:TG) on proton pump inhibitor (PPI) pharmacokinetics (PK) in children. The CYP2C:TG haplotype has been proposed to be associated with increased CYP2C19 activity. We sought to determine if this CYP2C:TG haplotype resulted in similar alterations in metabolism for proton pump inhibitors, which are primarily metabolized by CYP2C19. In a cohort of 41 children aged 6-21 participating in a PPI pharmacokinetic study, effects of the CYP2C:TG allele were assessed by fitting two linear regression models for each of the six PK outcomes assessed, the second of which accounted for the presence of the CYP2C:TG allele. The difference in R2 values between the two models was computed to quantify the variability in the outcome that could be accounted for by the CYP2C:TG allele after adjustment for the CYP2C19 genotype. We found the CYP2C:TG haplotype to have no measurable additive impact on CYP2C19-mediated metabolism of PPIs in vivo in older children and adolescents. The findings of this study do not support the clinical utility of routine testing for the CYP2C:TG haplotype to guide PPI dose adjustments in children.

Opportunities for Pharmacogenetic Testing to Guide Dosing of Medications in Youths With Medicaid.

Importance: There are an increasing number of medications with a high level of evidence for pharmacogenetic-guided dosing (PGx drugs). Knowledge of the prevalence of dispensings of PGx drugs and their associated genes may allow hospitals and clinical laboratories to determine which pharmacogenetic tests to implement. Objectives: To investigate the prevalence of outpatient dispensings of PGx drugs among Medicaid-insured youths, determine genes most frequently associated with PGx drug dispenses, and describe characteristics of youths who were dispensed at least 1 PGx drug. Design, Setting, and Participants: This serial cross-sectional study includes data from 2011 to 2019 among youths aged 0 to 17 years in the Marketscan Medicaid database. Data were analyzed from August to December 2022. Main Outcomes and Measures: PGx drugs were defined as any medication with level A evidence as determined by the Clinical Pharmacogenetics Implementation Consortium (CPIC). The number of unique youths dispensed each PGx drug in each year was determined. PGx drugs were grouped by their associated genes for which there was CPIC level A evidence to guide dosing, and a dispensing rate (No. of PGx drugs/100 000 youths) was determined for each group for the year 2019. Demographics were compared between youths dispensed at least 1 PGx drug and those not dispensed any PGx drugs. Results: The number of Medicaid-insured youths queried ranged by year from 2 078 683 youths in 2011 to 4 641 494 youths in 2017, including 4 126 349 youths (median [IQR] age, 9 [5-13] years; 2 129 926 males [51.6%]) in 2019. The proportion of Medicaid-insured youths dispensed PGx drugs increased from 289 709 youths (13.9%; 95% CI, 13.8%-14.0%) in 2011 to 740 072 youths (17.9%; 95% CI, 17.9%-18.0%) in 2019. Genes associated with the most frequently dispensed medications were CYP2C9, CYP2D6, and CYP2C19 (9197.0 drugs [95% CI, 9167.7-9226.3 drugs], 8731.5 drugs [95% CI, 8702.5-8759.5 drugs], and 3426.8 drugs [95% CI, 3408.1-3443.9 drugs] per 100 000 youths, respectively). There was a higher percentage of youths with at least 1 chronic medical condition among youths dispensed at least 1 PGx drug (510 445 youths [69.0%; 95% CI, 68.8%-69.1%]) than among 3 386 277 youths dispensed no PGx drug (1 381 544 youths [40.8%; 95% CI, 40.7%-40.9%) (P < .001) in 2019. Conclusions and Relevance: In this study, there was an increasing prevalence of dispensings for PGx drugs. This finding suggests that pharmacogenetic testing of specific drug-gene pairs should be considered for frequently prescribed PGx drugs and their implicated genes.

Major Drug-Drug Interaction Exposure Among Medicaid-Insured Children in the Outpatient Setting.

BACKGROUND AND OBJECTIVES: Drug-drug interactions (DDIs) can cause adverse drug events, but little is known about DDI exposure in children in the outpatient setting. This study aimed to determine the prevalence of major DDI exposure and factors associated with higher DDI exposure rates among children in an outpatient setting. METHODS: We performed a cross-sectional study of children aged 0 to 18 years with ≥1 ambulatory encounter, and ≥2 dispensed outpatient prescriptions study using the 2019 Marketscan Medicaid database. DDIs (exposure to a major DDI for ≥1 day) and the adverse physiologic effects of each DDI were identified using DrugBank's interaction database. Primary outcomes included the prevalence and rate of major DDI exposure. We used logistic regression to assess patient characteristics associated with DDI exposure. We examined the rate of DDI exposures per 100 children by adverse physiologic effects category, and organ-level effects (eg, heart rate-corrected QT interval prolongation). RESULTS: Of 781 019 children with ≥2 medication exposures, 21.4% experienced ≥1 major DDI exposure. The odds of DDI exposure increased with age and with medical and mental health complexity. Frequently implicated drugs included: Clonidine, psychiatric medications, and asthma medications. The highest adverse physiologic effect exposure rate per 100 children included: Increased drug concentrations (14.6), central nervous system depression (13.6), and heart rate-corrected QT interval prolongation (9.9). CONCLUSIONS: One in 5 Medicaid-insured children with ≥2 prescription medications were exposed to major DDIs annually, with higher exposures in those with medical or mental health complexity. DDI exposure places children at risk for negative health outcomes and adverse drug events, especially in the harder-to-monitor outpatient setting.

Fifty Years of Unraveling the Clinical Pharmacology of Corticosteroids.

This review will highlight portions of Dr. William Jusko's and colleagues' work that affected the clinical use and study of corticosteroids in acute and chronic disease management. Selected publications related to corticosteroid pharmacokinetics and pharmacodynamics from the 1970s through today were included in this review, with a focus on the foundational human-based studies conducted in the 1970s-1990s. Dr. Jusko contributed significantly to early corticosteroid pharmacology across several domains including: 1) foundational corticosteroid pharmacokinetic methods and parameter development, 2) disease state-variation in corticosteroid pharmacokinetics, 3) drug interaction effects on corticosteroid pharmacokinetics, and 4) early corticosteroid pharmacodynamic studies. In an era where little was known about the pharmacokinetics and pharmacodynamics of corticosteroids, Dr. Jusko's work opened the eyes of researchers and clinicians to the potential for disease and drug interactions that could reduce or enhance the effects of corticosteroids. This significant body of work paved the way for alternative routes of administration that would be useful in concentrating the activity at the site of action and markedly reduced systemic drug exposure, minimizing the risk of adverse effects through application of the dose-sparing pharmacokinetic and pharmacodynamic principles.

Medicaid Expenditures among Children with Documented Obesity.

Background: Obesity rates continue to rise among children, but knowledge regarding medical expenditures of Medicaid enrollees with documented obesity is lacking. We aim to describe Medicaid expenditure patterns among children with documented obesity and determine the degree to which specific clinical characteristics and conditions contribute to high expenditures. Methods: We performed a retrospective cross-sectional analysis of children aged 2-17 years with a diagnosis code of obesity continuously enrolled in the 2017 Medicaid MarketScan database. Children were grouped based on annual expenditure percentiles: <80th, 80 to <95th, 95 to <99th, and ≥99th. Inpatient, outpatient, and pharmacy expenditures were analyzed. Covariates included demographics, common obesity comorbid conditions (e.g., hypertension), complex chronic conditions (CCCs), and mental health conditions (MHCs). Logistic regression assessed demographic and clinical characteristics associated with high-spending groups (≥95th%). Results: We identified 300,286 children with a diagnosis of obesity. The 1% of children with the highest spending accounted for 25.4% of annual expenditures among children with documented obesity. Annual expenditures in the highest spending groups were driven primarily by inpatient and outpatient mental health services. Characteristics associated with high-spending groups included the following: age 12-17 years, obesity comorbid conditions, and having ≥1 CCC or MHC. These associations increased with increasing number of CCCs or MHCs. Conclusions: Inpatient and outpatient mental health expenditures made up a large proportion of spending among Medicaid-enrolled children with documented obesity. Important drivers of cost in this population were medical complexity and comorbid MHCs. Future research is needed to determine if some of these costs are avoidable in children with obesity.

Polypharmacy among medicaid-insured children with and without documented obesity.

OBJECTIVE: Polypharmacy increases the risk of drug-drug interactions and adverse drug events. As obesity and rates of obesity-associated comorbid chronic conditions continue to rise, an improved understanding of whether children with obesity experience higher risk of polypharmacy is needed. This study aimed to compare chronic medication polypharmacy prevalence among children with and without a diagnosis of obesity. METHODS: We performed a cross-sectional examination of prescription data for children aged 2-18 years prescribed ≥1 chronic medication using the 2019 Marketscan Medicaid database. Children with documented obesity were identified using medical visit diagnosis codes. Chronic medications included any ≥30-day prescription with ≥2 dispensed refills. Polypharmacy was defined as the prescription of ≥2 chronic medications for ≥1 overlapping days. Chi-squared tests compared polypharmacy prevalence and the distribution of chronic medication classes between children with and without obesity. Logistic regression determined the adjusted odds ratio (aOR) of polypharmacy for children with obesity, adjusting for relevant demographic and clinical differences. RESULTS: Of 634,671 included children, 12.2% had documented obesity. More than one-half (52.7%) of children with obesity experienced polypharmacy compared with 47.6% of children without obesity (aOR 1.06 [95% confidence interval 1.04-1.08]). Chronic medication prescriptions, particularly for psychiatric and asthma medications, were more commonly prescribed among children with obesity than those without obesity. CONCLUSIONS: Children with documented obesity have higher polypharmacy prevalence than children without obesity. Clinicians must be aware of this risk and minimize inappropriate polypharmacy whenever possible. Future work should examine the consequences of polypharmacy, including drug-drug interactions and adverse drug events in children with obesity.

Guideline-Concordant Antiviral Treatment in Children at High Risk for Influenza Complications.

BACKGROUND: National guidelines recommend antiviral treatment for children with influenza at high risk for complications regardless of symptom duration. Little is known about concordance of clinical practice with this recommendation. METHODS: We performed a cross-sectional study of outpatient children (aged 1-18 years) at high risk for complications who were diagnosed with influenza during the 2016-2019 influenza seasons. High-risk status was determined using an existing definition that includes age, comorbidities, and residence in a long-term care facility. The primary outcome was influenza antiviral dispensing within 2 days of influenza diagnosis. We determined patient- and provider-level factors associated with guideline-concordant treatment using multivariable logistic regression. RESULTS: Of the 274 213 children with influenza at high risk for influenza complications, 159 350 (58.1%) received antiviral treatment. Antiviral treatment was associated with the presence of asthma (aOR, 1.13; 95% confidence interval [CI], 1.11-1.16), immunosuppression (aOR, 1.10; 95% CI, 1.05-1.16), complex chronic conditions (aOR, 1.04; 95% CI, 1.01-1.07), and index encounter in the urgent care setting (aOR, 1.3; 95% CI, 1.26-1.34). Factors associated with decreased odds of antiviral treatment include age 2-5 years compared with 6-17 years (aOR, 0.95; 95% CI, .93-.97), residing in a chronic care facility (aOR, .61; 95% CI, .46-.81), and index encounter in an emergency department (aOR, 0.66; 95% CI, .63-.71). CONCLUSIONS: Among children with influenza at high risk for complications, 42% did not receive guideline-concordant antiviral treatment. Further study is needed to elucidate barriers to appropriate use of antivirals in this vulnerable population.

Prevalence and Severity of Chronic Conditions among Adolescents with Obesity.

Childhood obesity prevalence continues to increase, and may be coupled with a rise in rates of chronic conditions tied to obesity. We compared the prevalence and severity of 14 chronic conditions between adolescents aged 10-17 years with and without obesity using the 2018-2019 National Survey of Children's Health (NSCH). Chi square tests assessed differences in chronic condition prevalence across weight groups, and logistic regression determined the odds of having chronic conditions in adolescents with versus without obesity. We found adolescents with obesity had higher prevalence of >85% of included chronic conditions. Those with obesity had higher odds of moderate/severe depression [adjusted odds ratio (aOR) 1.41, 95% confidence interval (CI) 1.01-1.96], autism spectrum disorder (aOR 2.07, 95% CI 1.2-3.57), and developmental delay (aOR 1.77, 95% CI 1.15-2.73). Awareness of the ties between having a chronic condition among adolescents with obesity may help providers in assessing risk of morbidity among this at-risk group of children.

Clinical Outcome and Antibiotic Dosing Differences by Weight in Children With Acute Osteomyelitis.

OBJECTIVES: To evaluate for weight-based differences in clinical outcomes and antibiotic dosing variability for children hospitalized with acute hematogenous osteomyelitis (AHO). METHODS: We performed a retrospective cohort study of children aged 2 to 17 years and hospitalized with a primary AHO International Classification of Diseases, Ninth Revision or International Classification of Diseases, 10th Revision diagnosis code between 2010 and 2017 using the Cerner Health Facts database. Weight categories (healthy, overweight, obesity) were determined by using Centers for Disease Control and Prevention age- and sex-specific BMI percentiles. Rates of procedures, complications, and length of stay (LOS) were compared between groups. Dosing variability between groups was assessed by comparing the initial milligrams per kilogram per day of prescribed antibiotics. RESULTS: We identified 755 children with AHO for inclusion. Children with overweight and obesity were more likely to undergo surgical procedures (19% and 17%, respectively) compared with children with a healthy weight (10%; P = .009). They also had a longer LOS (5.7 and 5.8 days) than children with a healthy weight (4.9 days; P = .03). There were no differences in complication rates between weight categories. Mean weight-adjusted daily dose for the most frequently prescribed antibiotics was different by weight category, with children in higher weight categories more likely to receive lower weight-based doses. CONCLUSIONS: Children with overweight and obesity hospitalized for AHO were more likely to undergo procedures, have longer LOS, and receive lower weight-based antibiotic dosing compared with children with a healthy weight. Our findings suggest that weight should be carefully considered when treating children with AHO.

Associations between Obesity and Adverse Childhood Experiences in the United States.

Background: Obesity leads to serious health consequences in children and is potentially associated with increased adverse childhood experiences (ACEs). Nationally representative studies examining associations between obesity and ACEs are lacking. Therefore, we aimed to determine the relationship between ACEs and childhood obesity. Methods: We performed a retrospective cross-sectional study of children 10-17 years of age, who participated in the 2018 National Survey of Children's Health (NSCH), a national population-based survey. Obesity was determined by CDC definitions using BMI calculated by the NSCH from self-reported height/weight. Logistic regression, adjusted for key sociodemographic factors, determined differences in rates of ACEs between children with obesity (BMI ≥95th percentile) and those without (BMI <95th percentile). Results: Weighted NSCH data included 29,696,808 children 10-17 years of age, 15% with obesity. Obesity was associated with having more ACEs compared to other children (p < 0.01). In adjusted analyses, children with obesity were more likely than other children to report most ACEs, including food/housing insecurity [adjusted odds ratio (aOR) 1.64, confidence interval (95% CI) 1.26-2.13], parental divorce [1.67 (1.32-2.13)], witnessing physical violence [1.49 (1.03-2.16)], be a victim of violence [1.99, (1.27-3.12)], or live with a person with drug/alcohol abuse [1.65, (1.24-2.2)]. Children with obesity were also more likely to report ≥4 ACEs compared to other children (p < 0.001). Conclusion: Children with obesity are more likely to report ACEs overall and have more ACEs compared to other children. Obesity negatively affects child health; in combination with ACEs, health outcomes of children may be disproportionately affected, highlighting the importance of preventive screening and social interventions in childhood.

Obesity and Corticosteroid Dosing Guideline Adherence in Children Hospitalized With Asthma.

OBJECTIVES: Drug dosing recommendations for children with obesity remain limited. This may lead to variability in medication dosing among children with obesity. Therefore, our objective was to determine differences in the prevalence of guideline-nonadherent systemic corticosteroid orders by weight category in children hospitalized for asthma. METHODS: We performed a retrospective cross-sectional study of children aged 2 to 17 years hospitalized with asthma and prescribed systemic corticosteroids between January 1, 2010, and December 31, 2017, using the Cerner Health Facts deidentified database. Weight categories ranging from underweight to class III obesity were defined on the basis of BMI percentiles by using CDC guidelines. Corticosteroid orders were categorized as guideline adherent or nonadherent on the basis of total body weight-based dosing guidelines from the National Heart, Lung, and Blood Institute. χ2 test and multivariable logistic regression models were used to determine differences in guideline adherence between weight categories. RESULTS: We identified 21 488 children prescribed systemic corticosteroids during asthma hospitalizations. Most (54.2%) had a healthy weight, and 23.8% had obesity. Almost one-quarter received guideline-nonadherent orders (22.2%), with increasing prevalence among higher weight categories (19.4% of healthy weight children versus 36.0% of those with class III obesity; P < .001). After controlling for demographic and clinical covariates, weight category remained significantly associated with receiving a guideline-nonadherent order (P < .001). CONCLUSIONS: The prevalence of guideline-nonadherent corticosteroid orders for children hospitalized with asthma increases linearly with weight category, disproportionately affecting children with severe obesity. Standardization of drug dosing guidelines for children with obesity may help reduce variability in drug doses prescribed that may increase risk of harm.

Associations Between Obesity and Use for Pediatric Hospitalizations.

BACKGROUND: Obesity is associated with poor outcomes for specific clinical groups of hospitalized children, but few data exist on outcomes of children with obesity on a larger scale during hospitalization. Therefore, we aimed to determine if use outcomes differ between hospitalized children with obesity and hospitalized children without obesity. METHODS: We performed a retrospective longitudinal cohort study of all children aged 2 to 19 years hospitalized at a single academic institution between January 1, 2009, and December 31, 2016. BMI was calculated from documented height and weight; obesity was defined by using age- and sex-specific BMI percentile guidelines from the Centers for Disease Control and Prevention. Only All Patient Refined Diagnosis-Related Groups (APR-DRGs) with >100 admissions during the study period were included. Primary outcome measures included hospital length of stay, hospital cost, and 14-day readmission. Generalized linear and logistic models were used to determine adjusted differences for outcome measures between patients with and without obesity. RESULTS: Of 78 756 included hospitalizations, obesity rates increased from 16.5% in 2009-2010 to 17.3% in 2015-2016 (P = .002). Only 6 (4.7%) of the 128 APR-DRGs examined were associated with increased use for patients with obesity: spinal procedures, tonsil and adenoid procedures, major respiratory procedures, peptic ulcer and gastritis, other musculoskeletal diagnoses, and other kidney and urinary tract diagnoses. There were no APR-DRGs with increased length of stay for children with obesity. CONCLUSIONS: Obesity is associated with increased hospitalization cost and readmission rates for a minority of diagnosis groups. Some groups of hospitalized children with obesity may benefit from targeted interventions to reduce obesity-specific risks. Future research should be focused on disparities in other relevant clinical outcomes.

Room Costs for Common Pediatric Hospitalizations and Cost-Reducing Quality Initiatives.

BACKGROUND: Improvement initiatives promote safe and efficient care for hospitalized children. However, these may be associated with limited cost savings. In this article, we sought to understand the potential financial benefit yielded by improvement initiatives by describing the inpatient allocation of costs for common pediatric diagnoses. METHODS: This study is a retrospective cross-sectional analysis of pediatric patients aged 0 to 21 years from 48 children's hospitals included in the Pediatric Health Information System database from January 1, 2017, to December 31, 2017. We included hospitalizations for 8 common inpatient pediatric diagnoses (seizure, bronchiolitis, asthma, pneumonia, acute gastroenteritis, upper respiratory tract infection, other gastrointestinal diagnoses, and skin and soft tissue infection) and categorized the distribution of hospitalization costs (room, clinical, laboratory, imaging, pharmacy, supplies, and other). We summarized our findings with mean percentages and percent of total costs and used mixed-effects models to account for disease severity and to describe hospital-level variation. RESULTS: For 195 436 hospitalizations, room costs accounted for 52.5% to 70.3% of total hospitalization costs. We observed wide hospital-level variation in nonroom costs for the same diagnoses (25%-81% for seizure, 12%-51% for bronchiolitis, 19%-63% for asthma, 19%-62% for pneumonia, 21%-78% for acute gastroenteritis, 21%-63% for upper respiratory tract infection, 28%-69% for other gastrointestinal diagnoses, and 21%-71% for skin and soft tissue infection). However, to achieve a cost reduction equal to 10% of room costs, large, often unattainable reductions (>100%) in nonroom cost categories are needed. CONCLUSIONS: Inconsistencies in nonroom costs for similar diagnoses suggest hospital-level treatment variation and improvement opportunities. However, individual improvement initiatives may not result in significant cost savings without specifically addressing room costs.

Opioid Use to Treat Migraine Headaches in Hospitalized Children and Adolescents.

OBJECTIVES: Prescription of opioids to treat pediatric migraine is explicitly discouraged by treatment guidelines but persists in some clinical settings. We sought to describe rates of opioid administration in pediatric migraine hospitalizations. METHODS: Using data from the Pediatric Health Information System, we performed a cross-sectional study to investigate the prevalence and predictors of opioid administration for children aged 7 to 21 years who were hospitalized for migraine between January 1, 2016, and December 31, 2018. RESULTS: There were 6632 pediatric migraine hospitalizations at 50 hospitals during the study period, of which 448 (7%) had an opioid administered during the hospitalization. There were higher adjusted odds of opioid administration in hospitalizations for non-Hispanic black (adjusted odds ratio [aOR], 1.68; P < .001) and Hispanic (aOR, 1.54; P = .005) (reference white) race and ethnicity, among older age groups (18-21 years: aOR, 2.74; P < .001; reference, 7-10 years), and among patients with higher illness severity (aOR, 2.58; P < .001). Hospitalizations during which an opioid was administered had a longer length of stay (adjusted rate ratio, 1.48; P < .001) and higher 30-day readmission rate (aOR, 1.96; P < .001). By pediatric hospital, opioid administration ranged from 0% to 23.5% of migraine hospitalizations. Hospitals with higher opioid administration rates demonstrated higher adjusted readmission rates (P < .001) and higher adjusted rates of return emergency department visits (P = .026). CONCLUSIONS: Opioids continue to be used during pediatric migraine hospitalizations and are associated with longer lengths of stay and readmissions. These findings reveal important opportunities to improve adherence to migraine treatment guidelines and minimize unnecessary opioid exposure, with the potential to improve hospital discharge outcomes.