To evaluate the impact of obesity on etanercept (ETN) drug exposure in children with juvenile idiopathic arthritis (JIA).
We conducted a pilot, cross-sectional, observational study in a real-world ...cohort of children with JIA receiving ETN as standard of care from a single center. We analyzed the relationship between body size and ETN plasma concentrations, adjusting for dosage. Body size was analyzed as a continuous measure using weight and body mass index (BMI) percentiles and categorically using BMI percentile classifications according to the CDC guidelines.
We enrolled a total of 29 children. Each child provided one plasma sample for ETN concentration measurement, and all participants were receiving subcutaneous ETN dosed weekly. We observed that the ETN concentration normalized for dose decreased significantly as a function of weight (p = 0.004) and BMI percentile (p = 0.04). Similarly, we observed a progressive decline in mean and median dose-normalized concentrations across higher body size categories. Because of reaching maximum ETN dosage (50 mg), 7 of 8 children (87.5%) with obesity received a weight-based dosage < 0.8 mg/kg/dose.
We found that higher body weight and BMI percentile are significantly and negatively associated with ETN drug serum concentration, accounting for differences in dosing. Our data suggest that children who are obese may be routinely under-dosed using current dosing strategies. Inadequate dosing may increase the risk for therapeutic failure and long-term morbidity in a developing child. As a result, characterizing adequate drug exposure in children of all sizes is an important step toward precision dosing.
Adverse drug reactions are a concern for all clinicians who utilize medications to treat adults and children; however, the frequency of adult and pediatric adverse drug reactions is likely to be ...under-reported. In this age of genomics and personalized medicine, identifying genetic variation that results in differences in drug biotransformation and response has contributed to significant advances in the utilization of several commonly used medications in adults. In order to better understand the variability of drug response in children however, we must not only consider differences in genotype, but also variation in gene expression during growth and development, namely ontogeny. In this article, recommendations for systematically approaching pharmacogenomic studies in children are discussed, and several examples of studies that investigate the genomic and developmental contribution to adverse drug reactions in children are reviewed.
We designed and initiated a pilot comparative effectiveness study for juvenile localized scleroderma (jLS), for which there is limited evidence on best therapy. We evaluated the process we used, in ...relation to the specific protocol and to the general task of identifying strategies for implementing studies in rare pediatric diseases.
This was a prospective, multi-center, observational cohort study of 50 jLS patients initiating treatment, designed and conducted by the jLS group of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) from 2012 to 2015. A series of virtual and physical meetings were held to design the study, standardize clinical assessments, generate and refine disease activity and damage measures, and monitor the study. Patients were initiated on one of three standardized methotrexate-based treatment regimens (consensus treatment plans, CTPs) and monitored for 1 year. An optional bio-banking sub-study was included.
The target enrollment of 50 patients was achieved over 26 months at 10 sites, with patients enrolled into all CTPs. Enrolled patients were typical for jLS. Study eligibility criteria were found to perform well, capturing patients thought appropriate for treatment studies. Minor modifications to the eligibility criteria, primarily to facilitate recruitment for future studies, were discussed with consensus agreement reached on them by the jLS group. There were marked differences in site preferences for specific CTPs, with half the sites treating all their patients with the same CTP. Most patients (88%) completed the study, and 68% participated in the bio-banking substudy.
We demonstrate the feasibility of our approach for conducting comparative effectiveness research in a rare pediatric disease. Multi-center collaboration by dedicated investigators who met regularly was a key factor in the success of this project. Other factors that facilitate these studies include having a sufficient number of investigators to enroll in each regimen, and streamlining study approval and management.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Timely trial start-up is a key determinant of trial success; however, delays during start-up are common and costly. Moreover, data on start-up metrics in pediatric clinical trials are sparse. To ...expedite trial start-up, the Trial Innovation Network piloted three novel mechanisms in the trial titled Dexmedetomidine Opioid Sparing Effect in Mechanically Ventilated Children (DOSE), a multi-site, randomized, double-blind, placebo-controlled trial in the pediatric intensive care setting.
The three novel start-up mechanisms included: 1) competitive activation; 2) use of trial start-up experts, called site navigators; and 3) supplemental funds earned for achieving pre-determined milestones. After sites were activated, they received a web-based survey to report perceptions of the DOSE start-up process. In addition to perceptions, metrics analyzed included milestones met, time to start-up, and subsequent enrollment of subjects.
Twenty sites were selected for participation, with 19 sites being fully activated. Across activated sites, the median (quartile 1, quartile 3) time from receipt of regulatory documents to site activation was 82 days (68, 113). Sites reported that of the three novel mechanisms, the most motivating factor for expeditious activation was additional funding available for achieving start-up milestones, followed by site navigator assistance and then competitive site activation.
Study start-up is a critical time for the success of clinical trials, and innovative methods to minimize delays during start-up are needed. Milestone-based funds and site navigators were preferred mechanisms by sites participating in the DOSE study and may have contributed to the expeditious start-up timeline achieved.
ClinicalTrials.gov #: NCT03938857
•Three novel incentives reduced study start-up times in a multi-site clinical trial.•Funds assigned for achieving start-up milestones were favored by study sites.•Site navigators effectively guided sites through start-up.•Competitive activation was the least preferred incentive by study sites.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Despite the frequent utilization of biomarkers in medical practice, there is a relative paucity of information regarding validated pediatric biomarkers. Frequently, biomarkers found to be efficacious ...in adults are extrapolated to the pediatric clinical setting without considering that the pathogenesis of many diseases is distinctly different in children, and ontogeny directly influences disease evolution and therapeutic response in children. New and innovative approaches are necessary to provide reliable, validated biomarkers that can be used to improve and advance pediatric medical care.
Developmental pharmacogenomics Neville, Kathleen A.; Becker, Mara L.; Goldman, Jennifer L. ...
Pediatric anesthesia,
03/2011, Volume:
21, Issue:
3
Journal Article
Peer reviewed
Summary
Interindividual variability in the disposition and action associated with similar doses of a given medication is an inherent characteristic of both adult and pediatric populations. ...Genotype–phenotype relationships in infants and children must take into account the role that ontogeny plays in producing variability in both pharmacokinetics and pharmacodynamics. This review explores pharmacogenomics in the context of ontogeny and relates these to the expression of drug‐metabolizing enzymes and transporters and the consequent effect on the exposure–response relationship in the early years of life.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Adverse drug events are common in critically ill children and often result from systemic or target organ drug exposure. Methods of drug dosing and titration that consider pharmacokinetic ...alterations may improve our ability to optimally dose critically ill patients and reduce the risk for drug-related adverse events. To demonstrate this possibility, we explored the exposure-response relationship between midazolam and delirium in critically ill children. We retrospectively examined electronic health records (EHRs) of critically ill children <18 years of age hospitalized in the pediatric intensive care unit at Duke University; these children were administered midazolam during mechanical ventilation and had ≥1 Cornell Assessment of Pediatric Delirium (CAPD) score. We used individual-level data extracted from the EHR and a previously published population pharmacokinetic (PK) model developed in critically ill children to simulate plasma concentrations at the time of CAPD scores in 1,000 representative datasets. We used multilevel repeated measures models, with clustering at patient and simulation levels, to evaluate the associations between measures of drug exposure (e.g., concentration and area under concentration time curve) and delirium scores. We included 61 children, median age 1.5 years (range = 0.1–16.3), with 181 CAPD assessments. We identified similarities between simulated Empirical Bayesian parameter estimates from the EHR cohort and those from the PK model population. We identified a stronger association between drug concentration at the time of score and CAPD scores (coefficient 1.78; 95% confidence interval: 1.66–1.90) compared with cumulative dose per kilogram and CAPD scores (coefficient −0.01; 95% confidence interval: −0.01 to −0.01). EHR and PK models can be leveraged to investigate exposure-response relationships in critically ill children.
Objective
To create a pediatric rheumatology Top 5 list as part of the American Board of Internal Medicine Foundation's Choosing Wisely campaign.
Methods
Delphi surveys of a core group of ...representative pediatric rheumatology providers from across North America generated candidate Top 5 items. Items with high content agreement and perceived to be of prevalent use and of high impact were included in a survey of all American College of Rheumatology (ACR) members who identified themselves as providing care to pediatric patients. Items with the highest ratings were subjected to literature review and further evaluation.
Results
A total of 121 candidate items were proposed in the initial Delphi survey and were reduced to 28 items in subsequent surveys. These 28 items were sent to 1,198 rheumatology providers who care for pediatric patients, and 397 (33%) responded. Based upon survey data and literature review, the Top 5 items were identified. These items focused on testing for antinuclear antibodies, autoantibody panels, Lyme disease, methotrexate toxicity monitoring, and use of routine radiographs.
Conclusion
The ACR pediatric rheumatology Top 5 is one of the first pediatric subspecialty–specific Choosing Wisely Top 5 lists and provides an opportunity for patients and providers to discuss appropriate use of health care in pediatric rheumatology.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
OBJECTIVEMethotrexate (MTX) has several enzymatic targets in the folate pathway. To better understand the variability in response to MTX, we characterized the interindividual variability of ...intracellular folate pools in children with juvenile arthritis (JA) and determined clinical and genetic contributors to this variability.
STUDY DESIGNThis exploratory single-center cross-sectional study evaluated 93 patients with JA not currently receiving MTX. Whole blood, plasma, and erythrocyte folate concentrations were determined after deconjugation and analyzed through reversed-phase separation and stable isotope dilution tandem mass spectrometry. Folate polyglutamates were measured in red blood cell lysates using an ion-pair reversed phase chromatography tandem mass spectrometry method.
RESULTSIntracellular concentrations of 5-methyl-tetrahydrofolate (5-CH3-THF) and 5,10-methenyl-tetrahydrofolate varied approximately 20-fold and 80-fold, respectively. The polyglutamated forms of 5-CH3-THF as a percentage of total 5-CH3-THF (5-CH3-THFGlun) were also measured. Hierarchical clustering of 5-CH3-THFGlun revealed two groups, each with two distinct clusters. There was an inverse relationship between 5-CH3-THFGlun chain length and plasma 5-CH3-THF concentrations. A subgroup of patients with a historical intolerance to MTX had significantly lower cellular folate concentrations (P<0.0001). In univariate analyses, clinical variables including sex, age, and folate supplementation in addition to variations in MTHFR, MTR, and SLC25A32 were associated with differential intracellular folate redox concentrations. Multivariate analysis further supported the association of single nucleotide polymorphisms in SLC25A32, MTHFR, and MTR with variability in intracellular 5-CH3-THF and 5,10-methenyl-tetrahydrofolate concentrations, respectively.
CONCLUSIONMeasurement of intracellular folate isoforms may contribute toward a better understanding of individual MTX effects in JA. Clinical variables in addition to genotypic differences beyond MTHFR may additionally explain differential intracellular folate concentrations and variable responses to MTX.
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