Developmental aspects of midazolam metabolism

From fetal life through adolescence, dramatic changes in pharmacokinetics and pharmacodynamics occur as a consequence of organ maturation and changes in body composition associated with normal development. Accordingly, effective and safe drug therapy in preterm infants, neonates, infants,children and adolescents requires a thorough understanding of human developmental biology and the ontogeny of the processes that govern absorption, distribution, metabolism, excretion, and action of drugs. Physicians must be aware of these interindividual differences, when prescribing drugs. The research presented by this thesis provides an example of an integrated approach to critically examine the pharmacokinetics and pharmacodynamics of midazolam, a benzodiazepine that is finding expanded use in neonatal intensive care units

Towards an Experientialist Understanding of Journalism:Exploring Arts-based Research for Journalism Studies

In this paper, we explore the ways in which we can employ arts-based research methods to unpack and represent the diversity and complexity of journalistic experiences and (self) conceptualisations. We address the need to reconsider the ways in which we theorise and research the field of journalism. We thereby aim to complement the current methodologies, theories, and prisms through which we consider our object of study to depict more comprehensively the diversity of practices in the field. To gather stories about journalism creatively (and ultimately more inclusively and richly), we propose and present the use of arts-based research methods in journalism studies. By employing visual and narrative artistic forms as a research tool, we make room for the senses, emotion and imagination on the part of the respondents, researchers and audiences of the output. We draw on a specific collaboration with artists and journalists that resulted in a research event in which 32 journalists were invited to collaboratively recreate the "richness and complexity" of journalistic practices

Application to Add Midazolam to the Model List of Essential Medicines

Summary statement of the proposal for inclusion The benzodiazepine midazolam has proven sedative, anxiolytic and amnesic properties. It is extensively used for premedication and procedural sedation in both adults and children. In comparison to other benzodiazepine and non-benzodiazepine drugs, midazolam is equally or more effective for premedication/preoperative sedation. No evidence exists that premedication with midazolam prolongs discharge time from hospital. Its efficacy and safety have been extensively studied in both adults and children. This contrasts its comparator drug, diazepam for which data in children and elderly are scarce or lacking. Midazolam is also effective for procedural sedation as a single drug or in combination with an opioid. As a single drug, adequate sedation for procedures in the emergency room, is achieved in over 90% of all procedures. Comparative efficacy was shown for propofol. Data are insufficient to determine comparative efficacy for procedural sedation for other drugs. When administered with the appropriate precautions, e.g. titration to effect, adequate monitoring and personnel to support ventilation, midazolam is very safe. No major adverse events were seen in 847 adults who received midazolam for procedural sedation. Also, adverse effects can be antagonized with an effective antagonist, flumazenil. As midazolam is off-patent, drug costs are relatively low. Drug costs per procedure range from approximately 0.15 US$to 2.6 US$ in an adult, depending on dose and country, with significantly lower costs in developing countries

Pragmatic physiologically-based pharmacokinetic modeling to support clinical implementation of optimized gentamicin dosing in term neonates and infants: proof-of-concept

IntroductionModeling and simulation can support dosing recommendations for clinical practice, but a simple framework is missing. In this proof-of-concept study, we aimed to develop neonatal and infant gentamicin dosing guidelines, supported by a pragmatic physiologically-based pharmacokinetic (PBPK) modeling approach and a decision framework for implementation.MethodsAn already existing PBPK model was verified with data of 87 adults, 485 children and 912 neonates, based on visual predictive checks and predicted-to-observed pharmacokinetic (PK) parameter ratios. After acceptance of the model, dosages now recommended by the Dutch Pediatric Formulary (DPF) were simulated, along with several alternative dosing scenarios, aiming for recommended peak (i.e., 8–12 mg/L for neonates and 15–20 mg/L for infants) and trough (i.e., <1 mg/L) levels. We then used a decision framework to weigh benefits and risks for implementation.ResultsThe PBPK model adequately described gentamicin PK. Simulations of current DPF dosages showed that the dosing interval for term neonates up to 6 weeks of age should be extended to 36–48 h to reach trough levels <1 mg/L. For infants, a 7.5 mg/kg/24 h dose will reach adequate peak levels. The benefits of these dose adaptations outweigh remaining uncertainties which can be minimized by routine drug monitoring.ConclusionWe used a PBPK model to show that current DPF dosages for gentamicin in term neonates and infants needed to be optimized. In the context of potential uncertainties, the risk-benefit analysis proved positive; the model-informed dose is ready for clinical implementation

Review: Ontogeny of oral drug absorption processes in children

A large proportion of prescribed drugs to children are administered orally. Age-related change in factors affecting oral absorption can have consequences for drug dosing. Areas covered: For each process affecting oral drug absorption, a systematic search has been performed using Medline to identify relevant articles (from inception till February 2012) in humans. This review presents the findings on age-related changes of the following processes affecting oral drug absorption: gastric pH, gastrointestinal motility, bile salts, pancreatic function, intestinal pH, intestinal drug-metabolizing enzymes and transporter proteins. Expert opinion: Clinicians should bear in mind the ontogeny of oral drug absorption processes when prescribing oral drugs to children. The authors’ review shows large information gaps on almost all drug absorption processes. It is important that more knowledge is acquired on intestinal transit time, intestinal pH and the ontogeny of intestinal drug-metabolizing enzymes and drug transporter proteins. Furthermore, the ultimate goal in this field should be to predict more precisely the oral disposition of drugs in children across the entire pediatric age range

Striving for an effective but parsimonious use of sedation in pediatric intensive care

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Towards More Robust Evaluation of the Predictive Performance of Physiologically Based Pharmacokinetic Models:Using Confidence Intervals to Support Use of Model-Informed Dosing in Clinical Care

Background and ObjectiveWith the rise in the use of physiologically based pharmacokinetic (PBPK) modeling over the past decade, the use of PBPK modeling to underpin drug dosing for off-label use in clinical care has become an attractive option. In order to use PBPK models for high-impact decisions, thorough qualification and validation of the model is essential to gain enough confidence in model performance. Currently, there is no agreed method for model acceptance, while clinicians demand a clear measure of model performance before considering implementing PBPK model-informed dosing. We aim to bridge this gap and propose the use of a confidence interval for the predicted-to-observed geometric mean ratio with predefined boundaries. This approach is similar to currently accepted bioequivalence testing procedures and can aid in improved model credibility and acceptance.MethodsTwo different methods to construct a confidence interval are outlined, depending on whether individual observations or aggregate data are available from the clinical comparator data sets. The two testing procedures are demonstrated for an example evaluation of a midazolam PBPK model. In addition, a simulation study is performed to demonstrate the difference between the twofold criterion and our proposed method.ResultsUsing midazolam adult pharmacokinetic data, we demonstrated that creating a confidence interval yields more robust evaluation of the model than a point estimate, such as the commonly used twofold acceptance criterion. Additionally, we showed that the use of individual predictions can reduce the number of required test subjects. Furthermore, an easy-to-implement software tool was developed and is provided to make our proposed method more accessible.ConclusionsWith this method, we aim to provide a tool to further increase confidence in PBPK model performance and facilitate its use for directly informing drug dosing in clinical care

A User-Driven Framework for Dose Selection in Pregnancy:Proof of Concept for Sertraline

Despite growing knowledge of pregnancy-induced changes in physiology that may alter maternal and fetal pharmacokinetics, evidence-based antenatal doses are lacking for most drugs. Pharmacokinetic modeling and expanding clinical data in pregnancy may support antenatal doses. We aimed to develop and pilot a comprehensive and user-driven Framework for Dose Selection in Pregnancy to support the clinical implementation of a best-evidence antenatal dose for sertraline. After initial development and evaluation by experts, the framework prototype was piloted to formulate an antenatal dosing strategy for sertraline in depression and anxiety disorders. Next, the framework was reviewed and assessed for usability by a multidisciplinary working committee of end-users comprising healthcare practitioners, experts from other disciplines including pharmacometrics, reproductive toxicology and medical ethics, alongside pregnant women and a partner. The resulting framework encompasses the following: rationale for drug selection, a comprehensive analysis of pharmacokinetic and dose-related efficacy and safety data, and implementation aspects including feasibility and desirability of the recommended antenatal dose based on a structured maternal and fetal benefit-risk assessment. An antenatal dose recommendation for sertraline, as a case study, was formulated using this approach and endorsed for clinical use by the working committee. Future applications of the framework for other drugs can further demonstrate its suitability for developing best evidence, acceptable and clinically feasible antenatal doses