Quantifying the Pharmacodynamics of Morphine in the Treatment of Postoperative Pain in Preverbal Children
Sebastiaan C. GouloozeTirsa de KluisMonique van DijkIlse CeelieSaskia N. de WildtDick TibboelElke H. J. KrekelsCatherijne A. J. Knibbe
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Abstract While the pharmacokinetics of morphine in children have been studied extensively, little is known about the pharmacodynamics of morphine in this population. Here, we quantified the concentration‐effect relationship of morphine for postoperative pain in preverbal children between 0 and 3 years of age. For this, we applied item response theory modeling in the pharmacokinetic/pharmacodynamic analysis of COMFORT‐Behavior (COMFORT‐B) scale data from 2 previous clinical studies. In the model, we identified a sigmoid maximal efficacy model for the effect of morphine and found that in 26% of children, increasing morphine concentrations were not associated with lower pain scores (nonresponders to morphine up‐titration). In responders to morphine up‐titration, the COMFORT‐B score slowly decreases with increasing morphine concentrations at morphine concentrations >20 ng/mL. In nonresponding children, no decrease in COMFORT‐B score is expected. In general, lower baseline COMFORT‐B scores (2.1 points on average) in younger children (postnatal age <10.3 days) were found. Based on the model, we conclude that the percentage of children at a desirable COMFORT‐B score is maximized at a morphine concentration between 5 and 30 ng/mL for children aged <10 days, and between 5 and 40 ng/mL for children >10 days. These findings support a dosing regimen previously suggested by Krekels et al, which would put >95% of patients within this morphine target concentration range at steady state. Our modeling approach provides a promising platform for pharmacodynamic research of analgesics and sedatives in children.Keywords:
Pharmacodynamics
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Introduction: Children are at increased risk of medication-associated adverse events, often due to weight-based dosing errors. We aimed to reduce the proportion of medications that were administered where the dosing weight was ≥ 10% different from the recorded weight. Methods: We adopted in-situ usability testing to iteratively improve design of clinical decision support that would enable accurate dosing weight documentation by prompting clinicians to update weight if recorded weight was > 10% different and it had been at least 7 days since the last dosing weight update. Results: The proportion of medication administrations with difference >10% between their recorded weight and dosing weight decreased from 13.1% (56,256/ 429,006) in the baseline period to 9.5% (35,560 / 372,443) in the intervention period (P < 0.001). Discussion and Conclusion: User-centered design of an interruptive alert improved the accuracy of dosing weights during medication administrations without substantial alert burden. In-situ usability testing is an effective approach to rapidly obtain feedback from frontline users and iterate on the design to effect desired behavior changes
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Abstract A treatment gap exists for pediatric patients with renal impairment. Alterations in renal clearance and metabolism of drugs render standard dosage regimens inappropriate and may lead to drug toxicity, but these studies are not routinely conducted during drug development. The objective of this study was to examine the clinical evidence behind current renal impairment dosage recommendations for pediatric patients in a standard pediatric dosing handbook. The sources of recommendations and comparisons included the pediatric dosing handbook (Lexicomp), the U.S. Food and Drug Administration‐approved manufacturer’s labels, and published studies in the literature. One hundred twenty‐six drugs in Lexicomp had pediatric renal dosing recommendations. Only 14% (18 of 126) of Lexicomp pediatric renal dosing recommendations referenced a pediatric clinical study, and 15% of manufacturer's labels (19 of 126) described specific dosing regimens for renally impaired pediatric patients. Forty‐two products had published information on pediatric renal dosing, but 19 (45%) were case studies. When pediatric clinical studies were not referenced in Lexicomp, the renal dosing recommendations followed the adult and pediatric dosing recommendations on the manufacturer's label. Clinical evidence in pediatric patients does not exist for most renal dosing recommendations in a widely used pediatric dosing handbook, and the adult renal dosing recommendations from the manufacturer's label are currently the primary source of pediatric renal dosing information.
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Long term daily dosing for patients and families may be challenging due to food aversions, dosing protocols, and age of the patient. The few long term studies suggest that low quantity daily dosing is associated with passing higher dose challenges over the long term, whereas high dose maintenance may protect for longer avoidance intervals. We review the data for peanut and suggest several strategies for your patients.
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This chapter explains the rational behind the concept of pharmacokinetics-guided dosing and dashboards, and the expected benefit of dashboards in improving therapy with monoclonal antibodies in inflammatory disease. It outlines a brief description of the various dosing strategies (both the induction and maintenance phases). In four dosing strategies, induction phase doses were administered as a two-hour intravenous infusion fixed at 5 mg kg-1 at Weeks 0, 2, and 6 as per label recommendations. Maintenance phase doses varied depending on the strategy: label dosing, stepwise adaptive dosing, proportional adaptive dosing, and Bayesian adaptive dosing. The goal of adaptive dosing strategies using Bayesian systems is to identify a dose/dosing frequency that maximizes the likelihood of an individual patient achieving a target exposure associated with an improved clinical outcome. The development of Bayes dosing systems in inflammatory bowel diseases currently presents challenges in defining how the development and implementation of such devices are funded, reimbursed, and implemented clinically.
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Sensitivity and specificity of dosing alerts for dosing errors among hospitalized pediatric patients
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