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Flowchart of patient recruitment. ECMO, extra corporeal membrane oxygenation; IV, intravenous; PICU, pediatric intensive care unit; PMA, postmenstrual age.
Source publication
Midazolam is metabolized by the developmentally regulated intestinal and hepatic drug metabolizing enzyme cytochrome P450 (CYP) 3A4/5. It is frequently administered orally to children, yet knowledge is lacking on the oral bioavailability in term neonates up until 1 year of age. Furthermore, the dispositions of the major metabolites 1‐OH‐midazolam (...
Contexts in source publication
Context 1
... and a median postnatal age of 9.8 weeks (2 days-5.3 years)) (see Figure 1). Three-quarters were 0-6 months old. ...
Context 2
... relative standard error values of the parameter estimates were below 50%, indicating that the estimates could be obtained from the data with good precision. The diagnostic plots for the final model are presented in Figure S1 (oral data) and in Figure S2 (IV data). Both figures indicate that the model describes the obtained data accurately, upon both oral and IV administration, even though for the oral data more random variability is observed. ...
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Aims
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Citations
... Summary of the published data on the bioavailability of midazolam in neonates, infants, and children in relation to post-menstrual age (PMA). The circles with different fills represent different studies, black horizontal stripe is data from adult meta-analysis, no fill is Brussee et al. 38 black fill is Reed et al., 35 white fill is Payne et al., 34 light gray fill is de Wildt et al., 27 dark gray vertical stripe is von Groen et al. 36 and dark gray is Brussee et al. 28 and their size reflects the size of the study population. The vertical gray dashed line at 40 weeks PMA distinguishes studies mainly performed in preterm and from term neonates. ...
Pediatric physiologically‐based modeling in drug development has grown in the past decade and optimizing the underlying systems parameters is important in relation to overall performance. In this study, variation of clinical oral bioavailability of midazolam as a function of age is used to assess the underlying ontogeny models for intestinal CYP3A4. Data on midazolam bioavailability in adults and children and different ontogeny patterns for intestinal CYP3A4 were first collected from the literature. A pediatric PBPK model was then used to assess six different ontogeny models in predicting bioavailability from preterm neonates to adults. The average fold error ranged from 0.7 to 1.38, with the rank order of least to most biased model being No Ontogeny < Upreti = Johnson < Goelen < Chen < Kiss. The absolute average fold error ranged from 1.17 to 1.64 with the rank order of most to least precise being Johnson > Upreti > No Ontogeny > Goelen > Kiss > Chen. The optimal ontogeny model is difficult to discern when considering the possible influence of CYP3A5 and other population variability; however, this study suggests that from term neonates and older a faster onset Johnson model with a lower fraction at birth may be close to this. For inclusion in other PBPK models, independent verification will be needed to confirm these results. Further research is needed in this area both in terms of age‐related changes in midazolam and similar drug bioavailability and intestinal CYP3A4 ontogeny.
... Conversely, both drugs may trigger or aggravate abnormal adverse effects classically associated with alpha-2 adrenergic and imidazoline receptor agonists [21,28]. It is established, however, that even when imidazole derivatives are used as a nasal decongestant in children (with doses prescribed to adults), these medications can cause systemic toxic effects such as lethargy, bradycardia, miosis, hypotension, and respiratory depression [25,49,50]. In brief, the harmful effects of all imidazolines include central nervous system (CNS) depression [51]. ...
Accidental poisonings by ingesting conjunctival fluid mixed with eye drops commonly involve alpha-2 adrenergic receptor agonists and tetrahydrozoline. These substances are recognized in commonly reported ingestions. Victims of all ages, otherwise in good health, often present as pale and lethargic to the emergency department (ED) after unintentionally ingesting topical eye medication. While eye drop poisoning cases in childhood include accidents during the play and poisonings in adults mean either suicide attempts or side effects caused by the systemic absorption of the substance, fluid of the ocular surface is a risk to all age groups. With this in mind, this study aimed to summarize data in the literature on tetrahydrozoline and alpha-2 adrenergic receptor agonists as dangerous medications, even when administered in low-bioavailability forms, such as eye drops. With this aim, a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant systematic review of relevant studies was conducted. A search of PubMed, Scopus, Web of Science, and EBSCOhost yielded nine studies that met the rigorous inclusion criteria. The primary studies were subject to a meta-analysis once a quality appraisal of the studies and a narrative synthesis of the extracted data had been conducted. The author hopes that this information will provide observations that will lead to better designs for over-the-counter eye drops, off-label drug usage policies, and parental attention.
... Oral midazolam is the most popular method for pre-induction sedation. Due to the first-pass effect, the bioavailability of oral midazolam is relatively lower with large variability (Funk et al., 2000;van Groen et al., 2021), and the onset time is as long as 21.9 ± 5.34 min (Lammers et al., 2002). Intranasal medication, instead of the oral route, not only can avoid first-pass metabolism but also offers a rapid onset of therapeutic effects (Bitter et al., 2011) for the rich vascular plexus cavity, which communicates with the subarachnoid space via the olfactory or trigeminal nerve (Trevino et al., 2020). ...
... Due to the first-pass effect, the bioavailability of oral midazolam is relatively lower with large variability (Funk et al., 2000;van Groen et al., 2021), and the onset time is as long as 21.9 ± 5.34 min (Lammers et al., 2002). Intranasal medication, instead of the oral route, not only can avoid first-pass metabolism but also offers a rapid onset of therapeutic effects (Bitter et al., 2011) for the rich vascular plexus cavity, which communicates with the subarachnoid space via the olfactory or trigeminal nerve (Trevino et al., 2020). Oral midazolam, intranasal dexmedetomidine, and midazolam (Shen et al., 2022) are practicable, but they are not ideal for pre-induction sedation because of their slow onset or large variability (Wermeling et al., 2006;Baldwa et al., 2012;Nie et al., 2023). ...
Background
Most preschool children are distressed during anesthesia induction. While current pharmacological methods are useful, there is a need for further optimization to an “ideal” standard. Remimazolam is an ultra-short-acting benzodiazepine, and intranasal remimazolam for pre-induction sedation may be promising.
Methods
This study included 32 preschool children who underwent short and minor surgery between October 2022 and January 2023. After pretreatment with lidocaine, remimazolam was administered to both nostrils using a mucosal atomizer device. The University of Michigan Sedation Score (UMSS) was assessed for sedation 6, 9, 12, 15, and 20 min after intranasal atomization. We used Dixon’s up-and-down method, and probit and isotonic regressions to determine the 50% effective dose (ED50) and 95% effective dose (ED95) of intranasal remimazolam for pre-induction sedation. Results: Twenty-nine pediatric patients were included in the final analysis. The ED50 and ED95 of intranasal remimazolam for successful pre-induction sedation, when processed via probit analysis, were 0.65 (95% confidence interval [CI], 0.59–0.71) and 0.78 mg/kg (95% CI, 0.72–1.07), respectively. In contrast, when processed by isotonic regression, they were 0.65 (95% CI: 0.58–0.72 mg/kg) and 0.78 mg/kg (95% CI: 0.69–1.08 mg/kg), respectively. At 6 min after intranasal remimazolam treatment, 81.2% (13/16) of “positive” participants were successfully sedated with a UMSS ≧ 1. All the “positive” participants were successfully sedated within 9 min.
Conclusion
Intranasal remimazolam is feasible for preschool children with a short onset time. For successful pre-induction sedation, the ED50 and ED95 of intranasal remimazolam were 0.65 and 0.78 mg/kg, respectively.
... The time to maximum serum concentration after oral administration is 1-1.5 hours, with an elimination halflife ranging to almost 4 hours [2]. Oral bioavailability varies widely from 21% to 66%, therefore it should not be surprising to find significant unabsorbed medication in the stomach [3]. However, what is surprising in this case is the child's significant level of sedation, although it appeared on endoscopy that only a small amount had been absorbed. ...
... When children are brought to the operating room after receiving oral midazolam, there is no easily performed study that would demonstrate what proportion of medication has been absorbed, versus the amount that remains in the stomach. The clinician can reasonably expect that residual unabsorbed midazolam continues to be absorbed into the bloodstream, in keeping with traditionally accepted pharmacokinetics of oral medication [3]. We present this case to demonstrate that a child receiving oral premedication with midazolam may have an unexpectedly large volume of unabsorbed medication in the stomach, despite having the desired clinical effects. ...
Background
Oral midazolam is commonly administered to reduce anxiety in children presenting for medical procedures or surgery. It is unclear what volume of medication remains unabsorbed in the stomach when the child presents for anesthetic induction prior to these procedures. The presence of any significant residual medication in the stomach has significant clinical implications in the postoperative period.
Case presentation
A 5-year-old white Caucasian boy presented for upper gastrointestinal endoscopy after receiving oral midazolam liquid. Insertion of the endoscope into the stomach revealed a significant amount of unabsorbed medication remaining within the gastric cavity.
Conclusion
Clinicians should be aware that the sedative effects of midazolam may be present before the medication is fully absorbed. A significant amount of unabsorbed medication may be present in the stomach during medical procedures/surgery. This may continue to be absorbed in the intraoperative and postoperative period, with unwanted clinical effect.
... 18,19 Intestinal drug metabolism matures slowly, as exemplified by midazolam's decreasing bioavailability over the paediatric age range (reflecting increasing first pass metabolism in the intestine and liver), although nonmaturational factors also determine a significant part of the variability. 20 For example, Blake et al. illustrated that dextromethorphan and caffeine metabolism in infants were affected by the type of nutrition (human milk vs. formula). 21 For nonenteral administration routes that display an absorption phase, absorption kinetics relates to the drug diffusion rate as well as tissue perfusion rate (i.e. ...
... Studies characterising paracetamol, midazolam and ursochol PK are published. 20,[116][117][118] The recent FDA guidance on neonatal drug studies suggests to consider microdosing to explore ontogeny. 119 Moreover, a recent proof-of-concept study showed the feasibility to safely use a [ 14 C] microtracer to elucidate paediatric metabolite pathways, which may address the challenges discussed above. ...
Developmental pharmacology describes the impact of maturation on drug disposition (pharmacokinetics, PK) and drug effects (pharmacodynamics, PD) throughout the paediatric age range. This paper, written by a multidisciplinary group of experts, summarizes current knowledge, and provides suggestions to pharmaceutical companies, regulatory agencies and academicians on how to incorporate the latest knowledge regarding developmental pharmacology and innovative techniques into neonatal and paediatric drug development.
Biological aspects of drug absorption, distribution, metabolism and excretion throughout development are summarized. Although this area made enormous progress during the last two decades, remaining knowledge gaps were identified. Minimal risk and burden designs allow for optimally informative but minimally invasive PK sampling, while concomitant profiling of drug metabolites may provide additional insight in the unique PK behaviour in children. Furthermore, developmental PD needs to be considered during drug development, which is illustrated by disease‐ and/or target organ‐specific examples. Identifying and testing PD targets and effects in special populations, and application of age‐ and/or population‐specific assessment tools are discussed. Drug development plans also need to incorporate innovative techniques such as preclinical models to study therapeutic strategies, and shift from sequential enrolment of subgroups, to more rational designs.
To stimulate appropriate research plans, illustrations of specific PK/PD‐related as well as drug safety‐related challenges during drug development are provided. The suggestions made in this joint paper of the Innovative Medicines Initiative conect4children Expert group on Developmental Pharmacology and the European Society for Developmental, Perinatal and Paediatric Pharmacology, should facilitate all those involved in drug development.
... Based on midazolam and 1-hydroxymidazolam disposition following oral or intravenous midazolam administration, intrinsic gut wall and liver clearance were very low (0.0196 and 6.7 L/h, respectively). This results in a highly variable and high total oral bioavailability of 92.1% (range 67-95 %) in preterms and 66 (range 25-85 %) in stable, critically ill children, compared to 30 % in adults (Brussee et al., 2018b;van Groen et al., 2020). The exposure of 1-hydroxy-midazolam and its glucuronide was highest in the youngest, decreasing significantly with postnatal age (van Groen et al., 2020). ...
... This results in a highly variable and high total oral bioavailability of 92.1% (range 67-95 %) in preterms and 66 (range 25-85 %) in stable, critically ill children, compared to 30 % in adults (Brussee et al., 2018b;van Groen et al., 2020). The exposure of 1-hydroxy-midazolam and its glucuronide was highest in the youngest, decreasing significantly with postnatal age (van Groen et al., 2020). ...
The absorption of oral drugs is frequently plagued by significant variability with potentially serious therapeutic consequences. The source of variability can be traced back to interindividual variability in physiology, differences in special populations (age- and disease-dependent), drug and formulation properties, or food-drug interactions. Clinical evidence for the impact of some of these factors on drug pharmacokinetic variability is mounting: e.g. gastric pH and emptying time, small intestinal fluid properties, differences in pediatrics and the elderly, and surgical changes in gastrointestinal anatomy. However, the link of colonic factors variability (transit time, fluid composition, microbiome), sex differences (male vs. female) and gut-related diseases (chronic constipation, anorexia and cachexia) to drug absorption variability has not been firmly established yet. At the same time, a way to decrease oral drug pharmacokinetic variability is provided by the pharmaceutical industry: clinical evidence suggests that formulation approaches employed during drug development can decrease the variability in oral exposure. This review outlines the main drivers of oral drug exposure variability and potential approaches to overcome them, while highlighting existing knowledge gaps and guiding future studies in this area.
... This was illustrated by a recently developed pediatric absorption physiologically-based pharmacokinetic model (PBPK) [41]. At the same time, limited data from ex vivo studies on intestinal and hepatic CYP3A, as well as oral bioavailability PK data of midazolam (as marker of CYP3A) suggest a different intestinal vs hepatic maturation pattern than suggested by a physiology-based population PK model [49,50]. ...
Although oral drug delivery is the preferred administration route and has been used for centuries, modern drug discovery and development pipelines challenge conventional formulation approaches and highlight the insufficient mechanistic understanding of processes critical to oral drug absorption. This review presents the opinion of UNGAP scientists on four key themes across the oral absorption landscape: (1) specific patient populations, (2) regional differences in the gastrointestinal tract, (3) advanced formulations and (4) food-drug interactions. The differences of oral absorption in pediatric and geriatric populations, the specific issues in colonic absorption, the formulation approaches for poorly water-soluble (small molecules) and poorly permeable (peptides, RNA etc.) drugs, as well as the vast realm of food effects, are some of the topics discussed in detail. The identified controversies and gaps in the current understanding of gastrointestinal absorption-related processes are used to create a roadmap for the future of oral drug absorption research.
... 3 Bq/kg). 55 The bioavailability of midazolam was 66% with a large range of 25-85% for which no explanatory covariates could be identified. These findings were in line with the expected CYP3A ontogeny, in that older children and adults have a higher CYP3A activity-and, thus, a lower oral bioavailability 54 -than the population in the microtracer study, and vice versa for preterm neonates. ...
The disposition of a drug is driven by various processes, such as drug metabolism, drug transport, glomerular filtration and body composition. These processes are subject to developmental changes reflecting growth and maturation along the paediatric continuum. However, knowledge gaps exist on these changes and their clinical impact. Filling these gaps may aid better prediction of drug disposition and creation of age‐appropriate dosing guidelines. We present innovative approaches to study these developmental changes in relation to drug metabolism and transport. First, analytical methods such as including liquid chromatography–mass spectrometry for proteomic analyses allow quantitation of the expressions of a wide variety of proteins, e.g. membrane transporters, in a small piece of organ tissue. The latter is specifically important for paediatric research, where tissues are scarcely available. Second, innovative study designs using radioactive labelled microtracers allowed study—without risk for the child—of the oral bioavailability of compounds used as markers for certain drug metabolism pathways. Third, the use of modelling and simulation to support dosing recommendations for children is supported by both the European Medicines Agency and the US Food and Drug Administration. This may even do away with the need for a paediatric trial. Physiologically based pharmacokinetics models, which include age‐specific physiological information are, therefore, increasingly being used, not only to aid paediatric drug development but also to improve existing drug therapies.
Background
The exact median effective dose (ED50) of intranasal dexmedetomidine combined with oral midazolam sedation for magnetic resonance imaging (MRI) examination in children remains unknow and the aim of this study was to determine the ED50 of their combination.
Methods
This is a prospective dose-finding study. A total of 53 children aged from 2 months to 6 years scheduled for MRI examination from February 2023 to April 2023 were randomly divided into group D (to determine the ED50 of intranasal dexmedetomidine) and group M (to determine the ED50 of oral midazolam). The dosage of dexmedetomidine and midazolam was adjusted according to the modified Dixon’s up-and-down method, and the ED50 was calculated with a probit regression approach.
Results
The ED50 of intranasal dexmedetomidine when combined with 0.5 mg∙kg− 1 oral midazolam was 0.39 µg∙kg− 1 [95% confidence interval (CI) 0.30 to 0.46 µg∙kg− 1] while the ED50 of oral midazolam was 0.17 mg∙kg− 1 (95% CI 0.01 to 0.29 mg∙kg− 1) when combined with 1 µg∙kg− 1 intranasal dexmedetomidine. The sedation onset time of children with successful sedation in group D was longer than in group M (30.0[25.0, 38.0]vs 19.5[15.0, 35.0] min, P < 0.05). No other adverse effects were observed in the day and 24 h after medication except one dysphoria.
Conclusion
This drug combination sedation regimen appears suitable for children scheduled for MRI examinations, offering a more precise approach to guide the clinical use of sedative drugs in children.
Trial registration
Chinese Clinical Trial Registry, identifier: ChiCTR2300068611(24/02/2023).
Machine Learning (ML) is a fast-evolving field, integrated in many of today’s scientific disciplines. With the recent development of neural ordinary differential equations (NODEs), ML provides a new tool to model dynamical systems in the field of pharmacology and pharmacometrics, such as pharmacokinetics (PK) or pharmacodynamics. The novel and conceptionally different approach of NODEs compared to classical PK modeling creates challenges but also provides opportunities for its application. In this manuscript, we introduce the functionality of NODEs and develop specific low-dimensional NODE structures based on PK principles. We discuss two challenges of NODEs, overfitting and extrapolation to unseen data, and provide practical solutions to these problems. We illustrate concept and application of our proposed low-dimensional NODE approach with several PK modeling examples, including multi-compartmental, target-mediated drug disposition, and delayed absorption behavior. In all investigated scenarios, the NODEs were able to describe the data well and simulate data for new subjects within the observed dosing range. Finally, we briefly demonstrate how NODEs can be combined with mechanistic models. This research work enhances understanding of how NODEs can be applied in PK analyses and illustrates the potential for NODEs in the field of pharmacology and pharmacometrics.
