Background: Physiological changes in pregnancy may affect drug safety and efficacy, sometimes requiring dose adjustments. Pregnancy-adjusted doses, however, are missing for most medications. Increasingly, pharmacokinetic models can be used for antenatal dose finding. Given the novelty of this technique and questions regarding dose credibility, the acceptability of model-informed antenatal doses should be explored. Objective: We aimed to assess the willingness-to-use and preferred features for model-informed antenatal doses among healthcare practitioners (HCPs) and pregnant women in European countries. Methods: A cross-sectional, web-based study drawing on two open surveys was performed between 8 September and 30 November 2022. Each survey comprised statements drawn from prior focus groups, associated with Likert-scales. Themes included respondents’ information needs, search behaviours along with their willingness-to-use and preferred features for model-informed antenatal doses. The surveys were disseminated through professional societies, pregnancy websites and social media. A descriptive analysis was performed. Results: In total, 608 HCPs from different specialties and 794 pregnant women across 15 countries participated, with 81% of respondents across both groups in the Netherlands or Belgium. Among pregnant women, 31% were medical professionals and 85% used medication during pregnancy. Eighty-three percent of HCPs found current antenatal pharmacotherapy suboptimal and 97% believed that model-informed antenatal doses would enhance the quality of antenatal care. Most HCPs (93%) and pregnant women (75%) would be willing to follow model-informed antenatal doses. Most HCPs desired access to the evidence (88%), including from pharmacokinetic modelling (62%). Most pregnant women (96%) wanted to understand antenatal dosing rationales and to be involved in dosing decisions (97%). Conclusion: The willingness-to-use model-informed antenatal doses is high among HCPs and pregnant women provided that certain information needs are met.
Caffeine is frequently used to treat apnea of prematurity in preterm infants. Because caffeine has a narrow therapeutic window, plasma concentrations are generally monitored weekly. It would be advantageous to monitor this therapy without blood sampling; saliva might offer this possibility. Paired plasma–saliva and saliva–saliva observations were made in preterm infants (n = 140, gestational ages between 24 and 34 weeks) who received caffeine for the treatment of apnea of prematurity. Three methods were used to collect saliva: no stimulation, dilute citric acid on collection gauze, and dilute citric acid in the cheek pouch before collection. Plasma and saliva caffeine concentrations were determined using high-performance liquid chromatography (HPLC). For all collection methods, the plots of the plasma/saliva outcomes showed linear relationships. The correlation between caffeine concentration in plasma and saliva and the reproducibility of saliva sampling was better with stimulation of saliva production using citric acid in the cheek pouch (r = 0.89) than with no stimulation (r = 0.68) or with stimulation using citric acid on the collection swab (r = 0.79). Monitoring of caffeine therapy in saliva can be applied reliably for routine use in clinical practice, but its reliability and reproducibility depend on the saliva sampling method used; saliva stimulation with citric acid in the cheek pouch is the best method studied.
Clinical and Translational Science highlights original research that helps bridge laboratory discovery with the diagnosis and treatment of human disease.Research may appear as Articles, Commentaries, Point-Counterpoint, Phase Forwards, Reviews, or Tutorials.CTS also includes invited didactic content that covers the connections between clinical pharmacology and translational medicine.These additional features provide context for research articles and facilitate understanding for a wide array of individuals interested in clinical and translational science.CTS welcomes high quality, scientifi cally sound original manuscripts focused on clinical pharmacology and translational science, including animal, in vitro, in silico, and clinical studies supporting the breadth of drug discovery, development, regulation and clinical use of drugs.
Cardiopulmonary bypass (CPB) induces a systemic inflammatory response syndrome (SIRS) by factors such as contact of the blood with the foreign surface of the extracorporeal circuit, hypothermia, reduction of pulmonary blood flow during CPB and endotoxemia. SIRS is maintained in the postoperative phase, co-occurring with a counter anti-inflammatory response syndrome. Research on the effects of drugs administered before the surgery, especially in the induction phase of anesthesia, as well as drugs used during extracorporeal circulation, has revealed that they greatly influence these postoperative inflammatory responses. A better understanding of these processes may not only improve postoperative recovery but also enable tailor-made pharmacotherapy, with both health and economic benefits. In this review, we describe the pathophysiology of SIRS and counter anti-inflammatory response syndrome in the light of CPB in children and the influence of drugs used on these syndromes.
Various in vitro, animal, and limited human adult studies suggest a profound inhibitory effect of inflammation and disease on cytochrome P-450 3A (CYP3A)-mediated drug metabolism. Studies showing this relationship in critically ill patients are lacking, whereas clearance of many CYP3A drug substrates may be decreased, potentially leading to toxicity.To prospectively study the relationship between inflammation, organ failure, and midazolam clearance as a validated marker of CYP3A-mediated drug metabolism in critically ill children.From 83 critically ill children (median age, 5.1 mo [range, 0.02-202 mo]), midazolam plasma (n = 532), cytokine (e.g., IL-6, tumor necrosis factor-α), and C-reactive protein (CRP) levels; organ dysfunction scores (Pediatric Risk of Mortality II, Pediatric Index of Mortality 2, Pediatric Logistic Organ Dysfunction); and number of failing organs were prospectively collected. A population pharmacokinetic model to study the impact of inflammation and organ failure on midazolam pharmacokinetics was developed using NONMEM 7.3.In a two-compartmental pharmacokinetic model, body weight was the most significant covariate for clearance and volume of distribution. CRP and organ failure were significantly associated with clearance (P < 0.01), explaining both interindividual and interoccasional variability. In simulations, a CRP of 300 mg/L was associated with a 65% lower clearance compared with 10 mg/L, and three failing organs were associated with a 35% lower clearance compared with one failing organ.Inflammation and organ failure strongly reduce midazolam clearance, a surrogate marker of CYP3A-mediated drug metabolism, in critically ill children. Hence, critically ill patients receiving CYP3A substrate drugs may be at risk of increased drug levels and associated toxicity.
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.
