Pharmacokinetics-Based Pediatric Dose Evaluation and Optimization Using Saliva - A Case Study.

Understanding pharmacokinetics (PK) in children is a prerequisite to determine optimal pediatric dosing. As plasma sampling in children is challenging, alternative PK sampling strategies are needed. In this case study we evaluated the suitability of saliva as alternative PK matrix to simplify studies in infants, investigating metamizole, an analgesic used off-label in infants. Six plasma and 6 saliva PK sample collections were scheduled after a single intravenous dose of 10 mg/kg metamizole. Plasma/saliva pharmacometric (PMX) modeling of the active metabolites 4-methylaminoantipyrine (4-MAA) and 4-aminoantipyrine (4-AA) was performed. Various reduced plasma sampling scenarios were evaluated by PMX simulations. Saliva and plasma samples from 25 children were included (age range, 5-70 months; weight range, 8.7-24.8 kg). Distribution of metamizole metabolites between plasma and saliva was without delay. Estimated mean (individual range) saliva/plasma fractions of 4-MAA and 4-AA were 0.32 (0.05-0.57) and 0.57 (0.25-0.70), respectively. Residual variability of 4-MAA (4-AA) in saliva was 47% (28%) versus 17% (11%) in plasma. A simplified sampling scenario with up to 6 saliva samples combined with 1 plasma sample was associated with similar PK parameter estimates as the full plasma sampling scenario. This case study with metamizole shows increased PK variability in saliva compared to plasma, compromising its suitability as single matrix for PK studies in infants. Nonetheless, rich saliva sampling can reduce the number of plasma samples required for PK characterization, thereby facilitating the conduct of PK studies to optimize dosing in pediatric patients.

Evaluation of Pupillometry for CYP2D6 Phenotyping in Children Treated with Tramadol.

Following the contraindication of codeine use in children, increasing use of tramadol has been observed in pain management protocols. However, tramadol's pharmacokinetics (PK) and pharmacodynamics are influenced by cytochrome P450 (CYP)2D6 activity, similarly to codeine. Previous studies in adults have demonstrated a correlation between pupillary response and tramadol PK. Our objective was to evaluate pupillometry as a phenotyping method to assess CYP2D6 activity in children treated with tramadol. We included 41 children (mean age 11 years) receiving a first dose of tramadol (2 mg/kg) in the emergency room (ER) as part of their routine care. CYP2D6 phenotyping and genotyping were performed. The concentrations of tramadol and its active metabolite, M1, were measured, and static and dynamic pupillometry was conducted using a handheld pupillometer at the time of tramadol administration and during the ER stay. Pupillometric measurements were obtained for 37 children. Tramadol affected pupillary parameters, with a decrease in pupil diameter in 83.8% of children (p = 0.002) (mean decrease 14.1 ± 16.7%) and a decrease in reflex amplitude constriction in 78.4% (p = 0.011) (mean decrease 17.7 ± 34.5%) at T150 compared to T0. We were unable to identify a correlation between pupillometry measurements and CYP2D6 activity. Likely confounding factors include light intensity, pain, and stress, making the procedure less feasible in paediatric emergency settings.

Practice of CYP450 genotyping and phenotyping in children in a real-life setting.

Pharmacokinetics varies widely between children. Many factors play an important role in this variability, such as ontogeny, pharmacogenetics, gender, comorbidities, and drug-drug interactions. Significant work has already been done in adults to understand the impact of genetic polymorphisms on drug-metabolizing enzyme activity and drug response. Data remain poor in children due to ontogeny that impacts genotyping-phenotyping correlation and the difficulty enrolling children in prospective studies. Our study aimed to describe the use of cytochromes P450 (CYP) phenotyping and/or genotyping tests in children in a real-life setting and assess the correlation between the genotype and the phenotype. We reviewed the results of tests performed between January 2005 and December 2020. Fifty-two children were genotyped and/or phenotyped. Four patients were excluded from the present analysis as they only underwent ABCB1 genotyping, without CYP testing. Of the remainder, 18 underwent simultaneous CYP genotyping and phenotyping, while 17 underwent CYP genotyping only, and 13 underwent CYP phenotyping only. In all cases, investigations were performed after the following situations: insufficient clinical response to treatment, low plasma concentrations, and adverse drug reactions (ADR). The vast majority of cases were related to immunosuppressive or antipsychotic therapy. Genotyping and/or phenotyping explained or contributed to the aforementioned clinical events in 56% of cases. The correlation between the genotype and the phenotype showed variability depending on the assessed cytochrome. In several cases, the phenotype did not correspond to the genotype because of comedications. In conclusion, there is clearly value in guiding drug based on CYP activity in children.

Hydromorphone Prescription for Pain in Children-What Place in Clinical Practice?

While morphine is the gold standard treatment for severe nociceptive pain in children, hydromorphone is increasingly prescribed in this population. This review aims to assess available knowledge about hydromorphone and explore the evidence for its safe and effective prescription in children. Hydromorphone is an opioid analgesic similar to morphine structurally and in its pharmacokinetic and pharmacodynamic properties but 5-7 times more potent. Pediatric pharmacokinetic and pharmacodynamic data on hydromorphone are sorely lacking; they are non-existent in children younger than 6 months of age and for oral administration. The current data do not support any advantage of hydromorphone over morphine, both in terms of efficacy and safety in children. Morphine should remain the treatment of choice for moderate and severe nociceptive pain in children and hydromorphone should be reserved as alternative treatment. Because of the important difference in potency, all strategies should be taken to avoid inadvertent administration of hydromorphone when morphine is intended.

Usability Testing and Technology Acceptance of an mHealth App at the Point of Care During Simulated Pediatric In- and Out-of-Hospital Cardiopulmonary Resuscitations: Study Nested Within 2 Multicenter Randomized Controlled Trials.

BACKGROUND: Mobile apps are increasingly being used in various domains of medicine. Few are evidence-based, and their benefits can only be achieved if end users intend to adopt and use them. To date, only a small fraction of mobile apps have published data on their field usability and end user acceptance results, especially in emergency medicine. OBJECTIVE: This study aims to determine the usability and acceptance of an evidence-based mobile app while safely preparing emergency drugs at the point of care during pediatric in- and out-of-hospital cardiopulmonary resuscitations by frontline caregivers. METHODS: In 2 multicenter randomized controlled parent trials conducted at 6 pediatric emergency departments from March 1 to December 31, 2017, and 14 emergency medical services from September 3, 2019, to January 21, 2020, the usability and technology acceptance of the PedAMINES (Pediatric Accurate Medication in Emergency Situations) app were evaluated among skilled pediatric emergency nurses and advanced paramedics when preparing continuous infusions of vasoactive drugs and direct intravenous emergency drugs at pediatric dosages during standardized, simulation-based, pediatric in- and out-of-hospital cardiac arrest scenarios, respectively. Usability was measured using the 10-item System Usability Scale. A 26-item technology acceptance self-administered survey (5-point Likert-type scales), adapted from the Unified Theory of Acceptance and Use of Technology model, was used to measure app acceptance and intention to use. RESULTS: All 100% (128/128) of nurses (crossover trial) and 49.3% (74/150) of paramedics (parallel trial) were assigned to the mobile app. Mean total scores on the System Usability Scale were excellent and reached 89.5 (SD 8.8; 95% CI 88.0-91.1) for nurses and 89.7 (SD 8.7; 95% CI 87.7-91.7) for paramedics. Acceptance of the technology was very good and rated on average >4.5/5 for 5 of the 8 independent constructs evaluated. Only the image construct scored between 3.2 and 3.5 by both participant populations. CONCLUSIONS: The results provide evidence that dedicated mobile apps can be easy to use and highly accepted at the point of care during in- and out-of-hospital cardiopulmonary resuscitations by frontline emergency caregivers. These findings can contribute to the implementation and valorization of studies aimed at evaluating the usability and acceptance of mobile apps in the field by caregivers, even in critical situations. TRIAL REGISTRATION: ClinicalTrials.gov NCT03021122; https://clinicaltrials.gov/ct2/show/NCT03021122. ClinicalTrials.gov NCT03921346; https://clinicaltrials.gov/ct2/show/NCT03921346. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13063-019-3726-4.

Impact of a Mobile App on Paramedics' Perceived and Physiologic Stress Response During Simulated Prehospital Pediatric Cardiopulmonary Resuscitation: Study Nested Within a Multicenter Randomized Controlled Trial.

BACKGROUND: Out-of-hospital cardiac arrests (OHCAs) are stressful, high-stake events that are associated with low survival rates. Acute stress experienced in this situation is associated with lower cardiopulmonary resuscitation performance in calculating drug dosages by emergency medical services. Children are particularly vulnerable to such errors. To date, no app has been validated to specifically support emergency drug preparation by paramedics through reducing the stress level of this procedure and medication errors. OBJECTIVE: This study aims to determine the effectiveness of an evidence-based mobile app compared with that of the conventional preparation methods in reducing acute stress in paramedics at the psychological and physiological levels while safely preparing emergency drugs during simulated pediatric OHCA scenarios. METHODS: In a parent, multicenter, randomized controlled trial of 14 emergency medical services, perceived and physiologic stress of advanced paramedics with drug preparation autonomy was assessed during a 20-minute, standardized, fully video-recorded, and highly realistic pediatric OHCA scenario in an 18-month-old child. The primary outcome was participants' self-reported psychological stress perceived during sequential preparations of 4 intravenous emergency drugs (epinephrine, midazolam, 10% dextrose, and sodium bicarbonate) with the support of the PedAMINES (Pediatric Accurate Medication in Emergency Situations) app designed to help pediatric drug preparation (intervention) or conventional methods (control). The State-Trait Anxiety Inventory and Visual Analog Scale questionnaires were used to measure perceived stress. The secondary outcome was physiologic stress, measured by a single continuous measurement of the participants' heart rate with optical photoplethysmography. RESULTS: From September 3, 2019, to January 21, 2020, 150 advanced paramedics underwent randomization. A total of 74 participants were assigned to the mobile app (intervention group), and 76 did not use the app (control group). A total of 600 drug doses were prepared. Higher State-Trait Anxiety Inventory-perceived stress increase from baseline was observed during the scenario using the conventional methods (mean 35.4, SD 8.2 to mean 49.8, SD 13.2; a 41.3%, 35.0 increase) than when using the app (mean 36.1, SD 8.1 to mean 39.0, SD 8.4; a 12.3%, 29.0 increase). This revealed a 30.1% (95% CI 20.5%-39.8%; P<.001) lower relative change in stress response in participants who used the app. On the Visual Analog Scale questionnaire, participants in the control group reported a higher increase in stress at the peak of the scenario (mean 7.1, SD 1.8 vs mean 6.4, SD 1.9; difference: -0.8, 95% CI -1.3 to -0.2; P=.005). Increase in heart rate during the scenario and over the 4 drugs was not different between the 2 groups. CONCLUSIONS: Compared with the conventional method, dedicated mobile apps can reduce acute perceived stress during the preparation of emergency drugs in the prehospital setting during critical situations. These findings can help advance the development and evaluation of mobile apps for OHCA management and should be encouraged. TRIAL REGISTRATION: ClinicalTrials.gov NCT03921346; https://clinicaltrials.gov/ct2/show/NCT03921346. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13063-019-3726-4.

Case Report: Low Hematocrit Leading to Tacrolimus Toxicity.

Tacrolimus is a calcineurin inhibitor characterized by a narrow therapeutic index and high intra- and inter-individual pharmacokinetic variability. Therapeutic drug monitoring in whole-blood is the standard monitoring procedure. However, tacrolimus extensively binds to erythrocytes, and tacrolimus whole-blood distribution and whole-blood trough concentrations are strongly affected by hematocrit. High whole-blood tacrolimus concentrations at low hematocrit may result in high unbound plasma concentrations and increased toxicity. We present the case of a 16-year-old girl with kidney and liver transplant in whom low concentrations of tacrolimus in the context of low hematocrit led to significant increase in the dosage of tacrolimus and participate, along with a genetic polymorphism of ABCB1, in nephrotoxicity.

Impact of Inflammation on Cytochromes P450 Activity in Pediatrics: A Systematic Review.

BACKGROUND AND OBJECTIVE: Cytochromes P450 (CYP) are the major enzymes involved in hepatic metabolism of drugs. Personalization of treatment in pediatrics is a major challenge, as it must not only take into account genetic, environmental, and physiological factors but also ontogeny. Published data in adults show that inflammation had an isoform-specific impact on CYP activities and we aimed to evaluate this impact in the pediatric population. METHODS: Articles listed in PubMed through 7 January, 2021 that studied the impact of inflammation on CYP activities in pediatrics were included in this systematic review. Sources of inflammation, victim drugs (CYP involved), effect of drug-disease interactions, number and age of subjects, and study design were extracted. RESULTS: Twenty-seven studies and case reports were included. The impact of inflammation on CYP activities appeared to be age dependent and isoform-specific, with some drug-disease interactions having significant pharmacokinetic and clinical impact. For example, midazolam clearance decreases by 70%, while immunosuppressant and theophylline concentrations increase three-fold and two-fold with intensive care unit admission and infection. Cytochrome P450 activity appears to return to baseline level when the disease is resolved. CONCLUSIONS: Studies that have assessed the impact of inflammation on CYP activity are lacking in pediatrics, yet it is a major factor to consider to improve drug efficacy or safety. The scarce current data show that the impact of inflammation is isoform and age dependent. An effort must be made to improve the understanding of the impact of inflammation on CYP activities in children to better individualize treatment.

Effect of a Mobile App on Prehospital Medication Errors During Simulated Pediatric Resuscitation: A Randomized Clinical Trial.

Importance: Medication errors are a leading cause of injury and avoidable harm, affecting millions of people worldwide each year. Children are particularly susceptible to medication errors, but innovative interventions for the prevention of these errors in prehospital emergency care are lacking. Objective: To assess the efficacy of an evidence-based mobile app in reducing the occurrence of medication errors compared with conventional preparation methods during simulated pediatric out-of-hospital cardiac arrest scenarios. Design, Setting, and Participants: This nationwide, open-label, multicenter, randomized clinical trial was conducted at 14 emergency medical services centers in Switzerland from September 3, 2019, to January 21, 2020. The participants were 150 advanced paramedics with drug preparation autonomy. Each participant was exposed to a 20-minute, standardized, fully video-recorded, realistic pediatric out-of-hospital cardiac arrest cardiopulmonary resuscitation scenario concerning an 18-month-old child. Participants were tested on sequential preparations of 4 intravenous emergency drugs of varying degrees of preparation difficulty (epinephrine, midazolam, 10% dextrose, and sodium bicarbonate). Intervention: Participants were randomized (1:1 ratio) to the support of an app designed to assist with pediatric drug preparation (intervention; n = 74) or to follow conventional drug preparation methods without assistance (control; n = 76). Main Outcomes and Measures: The primary outcome was the rate of medication errors, defined as a failure in drug preparation according to predefined, expert consensus-based criteria. Logistic regression models with mixed effects were used to assess the effect of the app on binary outcomes. Secondary outcomes included times to drug preparation and delivery, assessed with linear regression models with mixed effects. Results: In total, 150 advanced paramedics (mean [SD] age, 35.6 [7.2] years; 101 men [67.3%]; mean [SD] time since paramedic certification, 8.0 [6.2] years) participated in the study and completed 600 drug preparations. Of 304 preparations delivered using the conventional method, 191 (62.8%; 95% CI, 57.1%-68.3%) were associated with medication errors compared with 17 of 296 preparations delivered using the app (5.7%; 95% CI, 3.4%-9.0%). When accounting for repeated measures, with the app, the proportion of medication errors decreased in absolute terms by 66.5% (95% CI, 32.6%-83.8%; P < .001), the mean time to drug preparation decreased by 40 seconds (95% CI, 23-57 seconds; P < .001), and the mean time to drug delivery decreased by 47 seconds (95% CI, 27-66 seconds; P < .001). The risk of medication errors varied across drugs with conventional methods (19.7%-100%) when compared with the app (4.1%-6.8%). Conclusions and Relevance: Compared with conventional methods, the use of a mobile app significantly decreased the rate of medication errors and time to drug delivery for emergency drug preparation in a prehospital setting. Dedicated mobile apps have the potential to improve medication safety and change practices in pediatric emergency medicine. Trial Registration: ClinicalTrials.gov Identifier: NCT03921346.

Amoxicillin Dosing Regimens for the Treatment of Neonatal Sepsis: Balancing Efficacy and Neurotoxicity.

INTRODUCTION: Large variability in neonatal amoxicillin dosing recommendations may reflect uncertainty about appropriate efficacy and toxicity targets. OBJECTIVE: The aim of this study was to model efficacious and safe exposure for current neonatal amoxicillin dosing regimens, given a range of assumptions for minimal inhibitory concentration (MIC), targeted %fT > MIC, and potential for aminopenicillin-related neurotoxicity. METHODS: Individual intravenous amoxicillin exposures based on 6 international and 9 Swiss neonatal dosing recommendations, reflecting the range of current dosing approaches, were assessed by a previously developed population pharmacokinetic model informed by neonatal data from an international cohort. Exposure was simulated by attributing each dosing regimen to each patient cohort. End points of interest were %fT > MIC and potential neurotoxicity using Cmax > 140 mg/L as threshold. RESULTS: None of the dosing regimens achieved targets of ≥100%fT > MIC at any of the relevant MICs for a desired probability of target attainment (PTA) of ≥90%. All regimens achieved a PTA ≥90% for Streptococcus agalactiae (MIC 0.25 mg/L) and Listeria monocytogenes (MIC 1 mg/L) when targeting ≤70%fT > MIC. In contrast, none of the regimens resulted in a PTA ≥90% targeting ≥70%fT > MIC for enterococci (MIC 4 mg/L). The maximum amoxicillin concentration associated with potential neurotoxicity was exceeded using 4 dosing regimens (100 mg/kg q12, 60/30 mg/kg q12/8, 50 mg/kg q12/8/6, and 50 mg/kg q12/8/4) for ≥10% of neonates. CONCLUSIONS: The acceptability of regimens is highly influenced by efficacy and toxicity targets, the selection of which is challenging. Novel randomized trial designs combined with pharmacometric modeling and simulation could assist in selecting optimal dosing regimens in this understudied population.

Viral Infections and Cutaneous Drug-Related Eruptions.

In the general population, up to 10% of children treated by antibiotics have cutaneous adverse drug reaction, but allergy is confirmed in less than 20% of patients. Most of the non-allergic reactions are probably due to virus, such as enterovirus acute infection or Ebstein-Barr Virus (EBV) acute infection or reactivation. Especially in children, viruses have the propensity to induce skin lesions (maculopapular rash, urticaria) due to their skin infiltration or immunologic response. In drug-related skin eruptions, a virus can participate by activating an immune predisposition. The culprit antibiotic is then the trigger for reacting. Even in severe drug-induced reactions, such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, viruses take part in immune phenomena, especially herpes viruses. Understanding the mechanisms of both virus- and drug-induced skin reaction is important to develop our clinical reflection and give an adaptive care to the patient. Our aim is to review current knowledge on the different aspects and potential roles of viruses in the different type of drug hypersensitivity reactions (DHR). Although major advances have been made those past year, further studies are needed for a better understanding of the link between viruses and DHR, to improve management of those patients.

Toward precision medicine in pediatric population using cytochrome P450 phenotyping approaches and physiologically based pharmacokinetic modeling.

The activity of drug-metabolizing enzymes (DME) shows high inter- and intra-individual variability. Genetic polymorphisms, exposure to drugs, and environmental toxins are known to significantly alter DME expression. In addition, the activity of these enzymes is highly age-dependent due to maturation processes that occur during development. Currently, there is a vast choice of phenotyping methods in adults using exogenous probes to characterize the activity of these enzymes. However, this can hardly be applied to children since it requires the intake of non-therapeutic xenobiotics. In addition, sampling may be challenging in the pediatric population for a variety of reasons: limited volume (e.g., blood), inappropriate sampling methods for age (e.g., urine), and metric requiring invasive or multiple blood samples. This review covers the main existing methods that can be used in the pediatric population to determine DME activity, with a particular focus on cytochrome P450 enzymes. Less invasive tools are described, including phenotyping using endogenous probes. Finally, the potential of pediatric model-informed precision dosing using physiologically based pharmacokinetic modeling is discussed.

A mobile device app to reduce prehospital medication errors and time to drug preparation and delivery by emergency medical services during simulated pediatric cardiopulmonary resuscitation: study protocol of a multicenter, prospective, randomized controlled trial.

BACKGROUND: Emergency drug preparation and administration in children is both complex and time-consuming and places this population at a higher risk than adults for medication errors. Moreover, survival and a favorable neurological outcome from cardiopulmonary resuscitation are inversely correlated to drug preparation time. We developed a mobile device application (the pediatric Accurate Medication IN Emergency Situations (PedAMINES) app) as a step-by-step guide for the preparation to delivery of drugs requiring intravenous injection. In a previous multicenter randomized trial, we reported the ability of this app to significantly reduce in-hospital continuous infusion medication error rates and drug preparation time compared to conventional preparation methods during simulation-based pediatric resuscitations. This trial aims to evaluate the effectiveness of this app during pediatric out-of-hospital cardiopulmonary resuscitation. METHODS/DESIGN: We will conduct a multicenter, prospective, randomized controlled trial to compare the PedAMINES app with conventional calculation methods for the preparation of direct intravenously administered emergency medications during standardized, simulation-based, pediatric out-of-hospital cardiac arrest scenarios using a high-fidelity manikin. One hundred and twenty paramedics will be randomized (1:1) in several emergency medical services located in different regions of Switzerland. Each paramedic will be asked to prepare, sequentially, four intravenously administered emergency medications using either the app or conventional methods. The primary endpoint is the medication error rates. Enrollment will start in mid-2019 and data analysis in late 2019. We anticipate that the intervention will be completed in early 2020 and study results will be submitted in late 2020 for publication (expected in early 2021). DISCUSSION: This clinical trial will assess the impact of an evidence-based mobile device app to reduce the rate of medication errors, time to drug preparation and time to drug delivery during prehospital pediatric resuscitation. As research in this area is scarce, the results generated from this study will be of great importance and may be sufficient to change and improve prehospital pediatric emergency care practice. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03921346. Registered on 18 April 2019.

Dose evaluation of intravenous metamizole (dipyrone) in infants and children: a prospective population pharmacokinetic study.

PURPOSE: The prodrug metamizole is prescribed intravenously for postoperative pain in children, including off-label use in infants < 1 year. We aimed to assess the pharmacokinetics of the main metabolites of metamizole in children aged 3-72 months. METHODS: A single dose of 10 mg/kg metamizole was administered intravenously for postoperative analgesia. Pharmacokinetic samples were drawn at predefined time points. Pharmacokinetics of the main active metabolite 4-methylaminoantipyrine and three other metabolites was characterized by both non-compartmental and population pharmacokinetic analysis. AUC0-inf of 4-methylaminoantipyrine was calculated by non-compartmental analysis for two age cohorts (3-23 months, 2-6 years) and compared with the 80-125% range of adult dose-adjusted reference exposure (AUCref). Population pharmacokinetic analysis investigated age and weight dependency of the pharmacokinetics and optimal dosing strategies to achieve equivalent adult exposure. RESULTS: A total of 25 children aged 5 months-5.8 years (7.8-24.8 kg) with at least one concentration sample were included; 19 children had ≥ 5 predefined samples up to 10 h after metamizole dose administration. AUC0-inf of 4-methylaminoantipyrine in children 2-6 years was 29.9 mg/L/h (95% CI 23.4-38.2), significantly lower than AUCref (80-125% range 39.2-61.2 mg/L/h). AUC0-inf of 4-methylaminoantipyrine in infants < 2 years was 43.6 mg/L/h (95% CI 15.8-119.0), comparable with AUCref, while infants < 12 months showed increased exposure. Observed variability could be partially explained by covariates weight and age. CONCLUSIONS: Age-related changes in pharmacokinetics of 4-methylaminoantipyrine requires reduced weight-based IV dosing in infants < 1 year compared with infants and children up to 6 years (5 versus 10-20 mg/kg) to achieve equivalent adult exposure. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02660177 .

[Importance and specificity of pharmacovigilance in the pediatric population]. / Importance et particularités de la pharmacovigilance en pédiatrie.

Clinical trials are usually conducted in a limited time and on a selected population, most often excluding children. These clinical trials provide a first safety profile of the drugs, undeniably essential but often partial, highlighting only the most common adverse drug reactions. In addition in pediatrics, due to growth and physiologic maturation, adverse drug reactions may differ between children and adults and extrapolation of data obtained in adults to children, including safety data, may be inaccurate. Pharmacovigilance, which is based on spontaneous notifications of adverse drug reactions, helps to refine the risk/benefit ratio of drugs and to increase their safety after market launch. This article aims to highlight the importance of pharmacovigilance in general and in particular in the pediatric population and to remind the modalities of reporting in Switzerland.

Les essais cliniques sont le plus souvent effectués sur une durée limitée et une population sélectionnée, excluant les enfants. Ils fournissent un premier profil de sécurité des médicaments, souvent partiel, ne mettant en évidence que les effets indésirables les plus fréquents. En pédiatrie, les phénomènes de croissance et de maturation peuvent être à l'origine de réactions aux médicaments différentes que chez l'adulte et empêchent la simple extrapolation à l'enfant des données, notamment de sécurité, obtenues chez l'adulte. La pharmacovigilance repose sur la notification spontanée des effets indésirables. Elle permet d'affiner le rapport risques/bénéfices et d'augmenter la sécurité des médicaments une fois commercialisés. Cet article a pour but de souligner l'importance de la pharmacovigilance, en particulier dans la population pédiatrique, et de rappeler les modalités d'annonces.

Safety Issues of Pharmacological Acute Pain Treatment in Children.

Acute nociceptive pain management in children is a major public health concern. Effective and safe pain treatment is essential, but safety data cannot be simply extrapolated from adults to children due to pharmacokinetic and pharmacodynamic specificities. In addition, the frequent absence of child-specific data, the difficulty to assess drug tolerability, and the infants' inability to communicate properly and voluntarily report adverse drug reactions make children more vulnerable to safety issues. Awareness of the possible toxicity of analgesics is important but should not lead to suboptimal dosing and underuse of analgesia. A better assessment and individualization of treatment should allow effective prescribing of analgesics in more secure conditions. This article aims to review the safety of acetaminophen, nonsteroidal anti-inflammatory drugs, and opioids in children and the precautions that should be taken.

[Opioids prescription in the vulnerable populations : the children and the elderly. Practical guidelines]. / Prescription des opioïdes chez les patients vulnérables : les enfants et les personnes âgées. Recommandations pratiques.

Pain management in ambulatory care regularly requires the prescription of opioids. These drugs allow adequate analgesia achievement in many patients, but inefficiency and/or intolerable side effects may limit their use. Factors related to physiological particularities, comorbidities and comedication, as well as difficulties related to drug intake and pain assessment, make children and the elderly more vulnerable to variability in opioid response and problems of safety and efficacy profile. The purpose of this article is to remain the specificities of these two populations and to propose recommendations for the good use of opioids for ambulatory care.

La prise en charge de la douleur en médecine de ville nécessite régulièrement le recours à la prescription d'opioïdes. Une antalgie adéquate est obtenue chez de nombreux patients, mais une inefficacité et/ou des effets indésirables intolérables peuvent limiter leur utilisation. Les facteurs liés aux particularités physiologiques, aux comorbidités et aux comédications, les difficultés liées à la prise médicamenteuse et l'évaluation de la douleur, rendent l'enfant et le sujet âgé plus vulnérables à la variabilité de réponse aux opioïdes et aux problèmes de sécurité et d'efficacité. Le présent article a pour but de rappeler les spécificités de ces deux populations aux extrêmes de l'âge et de proposer des recommandations de bon usage des opioïdes pour la médecine ambulatoire.

When the Safe Alternative Is Not That Safe: Tramadol Prescribing in Children.

Children represent a vulnerable population in which management of nociceptive pain is complex. Drug responses in children differ from adults due to age-related differences. Moreover, therapeutic choices are limited by the lack of indication for a number of analgesic drugs due to the challenge of conducting clinical trials in children. Furthermore the assessment of efficacy as well as tolerance may be complicated by children's inability to communicate properly. According to the World Health Organization, weak opioids such as tramadol and codeine, may be used in addition to paracetamol and ibuprofen for moderate nociceptive pain in both children and adults. However, codeine prescription has been restricted for the last 5 years in children because of the risk of fatal overdoses linked to the variable activity of cytochrome P450 (CYP) 2D6 which bioactivates codeine. Even though tramadol has been considered a safe alternative to codeine, it is well established that tramadol pharmacodynamic opioid effects, efficacy and safety, are also largely influenced by CYP2D6 activity. For this reason, the US Food and Drug Administration recently released a boxed warning regarding the use of tramadol in children. To provide safe and effective tramadol prescription in children, a personalized approach, with dose adaptation according to CYP2D6 activity, would certainly be the safest method. We therefore recommend this approach in children requiring chronic or recurrent nociceptive pain treatment with tramadol. In case of acute inpatients nociceptive pain management, prescribing tramadol at the minimal effective dose, in a child appropriate dosage form and after clear instructions are given to the parents, remains reasonable based on current data. In all other situations, morphine should be preferred for moderate to severe nociceptive pain conditions.

Quantitative Analysis of Gentamicin Exposure in Neonates and Infants Calls into Question Its Current Dosing Recommendations.

Optimal dosing of gentamicin in neonates is still a matter of debate despite its common use. We identified gentamicin dosing regimens from eight international guidelines and seven Swiss neonatal intensive care units. The dose per administration, the dosing interval, the total daily dose, and the demographic characteristics between guidelines were compared. There was considerable variability with respect to dose (4 to 6 mg/kg), dosing interval (24 h to 48 h), total daily dose (2.5 to 6 mg/kg/day), and patient demographic characteristics that were used to calculate individualized dosing regimens. A model-based simulation study in 1071 neonates was performed to determine the achievement of efficacious peak gentamicin concentrations according to predefined MICs (Cmax/MIC ≥ 10) and safe trough concentrations (Cmin ≤ 2 mg/liter) with recommended dosing regimens. MIC targets of 0.5 and 1 mg/liter were used. Dosing optimization was performed giving priority to the first day of treatment and with the goal of simplifying dosing. Current gentamicin neonatal guidelines allow to achieve effective peak concentrations for MICs ≤ 0.5 mg/liter but not higher. Model-based simulations indicate that to attain peak gentamicin concentrations of ≥10 mg/liter, a dose of 7.5 mg/kg should be administered using an extended dosing interval regimen. Trough concentrations of ≤2 mg/liter can be maintained with a dosing interval of 36 to 48 h in neonates according to gestational and postnatal age. For treatment beyond 3 days, therapeutic drug monitoring is advised to maintain adequate serum concentrations.

Guidance to develop individual dose recommendations for patients on chronic hemodialysis.

INTRODUCTION: In addition to tailored clinical trials in patients on chronic hemodialysis (HD) during drug development, clinician-initiated post-marketing studies and case reports on individual pharmacokinetic (PK) assessments provide an important source of information about drug dialysability and individualized dose recommendations in this vulnerable population. Areas covered: First, factors that may alter drug exposure in HD patients are explained. Second, available regulatory and methodological guidelines for PK assessments in this population are summarized. Third, a 4-step approach is proposed to develop individual dose recommendations for HD patients receiving drugs without data from a PK study: (1) literature search, (2) model-based dosage decisions, (3) validation and refinement through concentration monitoring, and (4) publication of relevant observations. Fourth, clinician-initiated PK assessments and case reports to evaluate and individualize use of drugs in HD patients are reviewed, and recommendations to enhance their quality are discussed. Expert commentary: Guidance on collecting and reporting PK information in individual HD patients is warranted to ensure completeness and consistency of such PK studies. A checklist and template for easy-to-implement PK calculations and pharmacometric modeling is provided to facilitate evaluation and individualization of dosing strategies in these patients.