Incorporating Breastfeeding-Related Variability with Physiologically Based Pharmacokinetic Modeling to Predict Infant Exposure to Maternal Medication Through Breast Milk: a Workflow Applied to Lamotrigine

The version of record of this article, first published in The American Association of Pharmaceutical Scientists Journal (The AAPS Journal), is available online at Publisher’s website: http://dx.doi.org/10.1208/s12248-021-00599-5Current methods to assess risk in infants exposed to maternal medication through breast milk do not specifically account for infants most vulnerable to high drug exposure. A workflow applied to lamotrigine incorporated variability in infant anatomy and physiology, milk intake volume, and milk concentration to predict infant exposure. An adult physiologically based pharmacokinetic model of lamotrigine was developed and evaluated. The model was scaled to account for growth and maturation of a virtual infant population (n=100). Daily infant doses were simulated using milk intake volume and concentration models described by a nonlinear equation of weight-normalized intake across infant age and a linear function on the relationship of observed milk concentrations and maternal doses, respectively. Average infant plasma concentration at steady state was obtained through simulation. Models were evaluated by comparing observed to simulated infant plasma concentrations from breastfeeding infants based on a 90% prediction interval (PI). Upper AUC ratio (UAR) was defined as a novel risk metric. Twenty-five paired (milk concentrations measured) and 18 unpaired (milk concentrations unknown) infant plasma samples were retrieved from the literature. Forty-four percent and 11% of the paired and unpaired infant plasma concentrations were outside of the 90% PI, respectively. Over all ages (0–7 months), unpaired predictions captured more observed infant plasma concentrations within 90% PI than paired. UAR was 0.18–0.44 when mothers received 200 mg lamotrigine, suggesting that infants can receive 18–44% of the exposure per dose as compared to adults. UARs determined for further medications could reveal trends to better classify at-risk mother-infant pairs.Canadian Institutes of Health Research (CIHR); Project Grant; Award Number: PJT-159782 || Canadian Institutes of Health Research (CIHR); Frederick Banting and Charles Best Canada Graduate Scholarships Doctoral Award (CGS-D), a Canada Graduate Scholarship to Honour Nelson Mandela; Award Number: DF2-17144

Pharmacokinetics and Safety of Micafungin in Infants Supported With Extracorporeal Membrane Oxygenation

Candida is a leading cause of infection in infants on extracorporeal membrane oxygenation (ECMO). Optimal micafungin dosing is unknown in this population because ECMO can alter drug pharmacokinetics (PK)

Population Pharmacokinetics of Olanzapine in Children

Aims The aim of this study was to evaluate the population pharmacokinetics (PopPK) of olanzapine in children and devise a model-informed paediatric dosing scheme. Methods The PopPK of olanzapine was characterized using opportunistically collected plasma samples from children receiving olanzapine per standard of care for any indication. A nonlinear mixed effect modelling approach was employed for model development using the software NONMEM (v7.4). Simulations from the developed PopPK model were used to devise a paediatric dosing scheme that targeted comparable plasma exposures to adolescents and adults. Results Forty-five participants contributed 83 plasma samples towards the analysis. The median (range) postnatal age and body weight of participants were 3.8 years (0.2–19.2) and 14.1 kg (4.2–111.7), respectively. The analysis was restricted to pharmacokinetic (PK) samples collected following enteral administration (oral and feeding tube). A one-compartment model with linear elimination provided an appropriate fit to the data. The final model included the covariates body weight and postmenstrual age (PMA) on apparent olanzapine clearance (CL/F). Typical CL/F and apparent volume of distribution (scaled to 70 kg) were 16.8 L/h (21% RSE) and 663 L (13% RSE), respectively. Developed dosing schemes used weight-normalized doses for children ≤6 months postnatal age or \u3c15 kg and fixed doses for children ≥15 kg. Conclusion We developed a paediatric PopPK model for enterally-administered olanzapine. To our knowledge, this analysis is the first study to characterize the PK of olanzapine in participants ranging from infants to adolescents. Body weight and PMA were identified as influential covariates for characterizing developmental changes in olanzapine apparent clearance

Vancomycin Cerebrospinal Fluid Pharmacokinetics in Children with Cerebral Ventricular Shunt Infections

This study described the cerebrospinal fluid (CSF) exposure of vancomycin in 8 children prescribed intravenous vancomycin therapy for cerebral ventricular shunt infection. Vancomycin CSF concentrations ranged from 0.06 to 9.13 mg/L and the CSF: plasma ratio ranged from 0 to 0.66. Two children out of three with a staphylococcal CSF infection had CSF concentrations > minimal inhibitory concentration at the end of the dosing interval

Drug Prescriptions Requiring Compounding at a Canadian University Affiliated Pediatric Hospital: A Cross-Sectional Study

Despite ongoing international efforts, many drugs administered to children must be compounded from dosage forms designed for adults because they remain unavailable in commercial formulations that suit their needs. Even though oral drug compounding is common in pediatrics, the extent of this practice has not been well described in recent years. This cross-sectional and retrospective study was conducted at a Canadian university-affiliated, 484-bed, tertiary care pediatric hospital and its rehabilitation centre on two randomly selected days. A total of 606 hospitalized children with 5465 prescriptions were included. Overall, compounded drugs for enteral administration (CDEA) represented 13% of all prescriptions (enteral and parenteral) and 23% of prescriptions for enteral administration. Of the 390 prescribed drugs, 122 required compounding. CDEA were mostly liquids (n = 478 [67%]) and mainly included drugs of the central nervous (35%), cardiovascular (21%), and gastro-intestinal (12%) systems. Nearly half (N = 298 [49%]) of children had at least one CDEA prescribed in their medical file. Many CDEA are available as commercial products in other jurisdictions. Collaboration is needed between all stakeholders to make these drugs available to Canadian children

Profile of resistance to IVIG treatment in patients with Kawasaki disease and concomitant infection.

INTRODUCTION:Kawasaki disease (KD) can be associated with concomitant viral or bacterial infections. Children with persistent or recurrent fever 36 hours after the end of intravenous immunoglobulin (IVIG) are considered to be resistant to treatment and are at increased risk for coronary complications. Although concomitant infection does not affect coronary outcome, it is unknown how it influences the response to IVIG treatment. METHODOLOGY:Retrospective cohort study between 2008 and 2016 in a tertiary pediatric university hospital, including 154 children, of which 59 (38%) had concomitant infection. RESULTS:Children with concomitant infection were more likely to have fever 48 hours after initial IVIG treatment (36% vs 20%, p = 0.05) and to be treated with a second dose (33% vs 18%, p = 0.04). Children with infection had higher C-reactive protein at the time of diagnosis (148 vs 112 mg/L, p = 0.04), and 48 hours after IVIG administration (111 vs 59 mg/L, p = 0.003). Nevertheless, there was no statistically significant difference in the prevalence of coronary complications (Z-score > 2.5) between children with and without concomitant infection (36% vs 39%, p = 0.68). CONCLUSION:Children with KD and concomitant infection are more likely to have persistent fever and elevated inflammatory markers after treatment. This association increases the likelihood of receiving a second dose of IVIG but not the risk of coronary complication. Accordingly, prospective studies to distinguish true IVIG resistance from infection induced persistent fever is warranted

Providing Suitable Pediatric Formulations for Canadian Children: A Call for Action

Background: Many medications given to children have no commercially available, age-appropriate formulations. This leads to manipulation of dosage forms designed for adults (compounding), which can result in an increased risk of dosing errors and adverse events, lack of medication adherence because of taste issues, and suboptimal dosing with therapeutic failure.Objectives: To determine which drugs required compounding for oral administration to children in a Canadian hospital and, for each compounded drug, to determine whether it was available as licensed oral pediatric formulations in the United States or the European Union.Methods: Drugs requiring compounded liquid formulations for oral administration, dispensed from January 1 to December 31, 2015, at a Canadian university-affiliated tertiary pediatric hospital, and prepared in a quantity exceeding 0.5 L per year, were retrospectively identified. The online drug databases of Health Canada, the US Food and Drug Administration, the European Medicines Agency (EMA), and the UK Medicines and Healthcare Products Regulatory Agency were searched to determine the availability of child-friendly oral formulations for these drugs. The regulatory status in each jurisdiction was also compared. For licensed formulations with potential concerns about excipient safety, EMA guidelines for sorbitol, propylene glycol, ethanol, and sodium benzoate were used to determine pediatric suitability.Results: Of the 56 compounded drugs investigated, 27 (48%) had a suitable commercialized child-friendly formulation available outside Canada. Overall, these drugs had been on the Canadian market for a median of 35 years, and almost half (27 [48%]) had a pediatric indication in Canada.Conclusions: Canada is lagging behind the United States and the European Union in ensuring availability of and access to suitable pediatric formulations. Potential explanations for this gap include small market size, regulatory uncertainties, and reimbursement shortcomings. Steps must be taken to implement pediatric-sensitive regulations and incentives, as well as reimbursement policies, to address these unmet needs.Keywords: compounding, child-friendly medicines, pediatric oral medicinesRÉSUMÉContexte : Plusieurs médicaments administrés aux enfants ne sont pas disponibles commercialement sous une forme pharmaceutique adaptée à leur âge. Ceci entraîne une manipulation des formes destinées aux adultes (préparation magistrale) et peut conduire à une augmentation du risque d’erreurs de dosage et d’effets indésirables, un manque d’observance médicamenteuse secondairement à des problèmes de goût, et un dosage sous-optimal associé à des échecs thérapeutiques.Objectifs : Définir les médicaments qui exigent une préparation magistrale pour être administrés par voie orale aux enfants dans un hôpital canadien et, pour chaque médicament faisant l’objet d’une préparation magistrale, déterminer s’il est disponible sous une forme pharmaceutique orale autorisée pour les enfants aux États-Unis ou dans l’Union européene.Méthodes : Les médicaments nécessitant des préparations magistrales liquides pour administration orale, distribués entre le 1er janvier et le 31 décembre 2015 dans un hôpital de soins pédiatriques tertiaires affilié à une université canadienne et dont la quantité préparée était supérieure à 0.5 L par an, ont été déterminés rétrospectivement. Les bases de données en ligne de médicaments de Santé Canada, de la Food and Drug Administration américaine, de l’Agence européenne des médicaments (AEM) et de la Medicines and Healthcare Products Regulatory Agency (Royaume-Uni) ont été interrogées pour déterminer la disponibilité de formes pharmaceutiques orales adaptées aux enfants pour ces médicaments. Le statut réglementaire de chaque pays a également fait l’objet d’une comparaison. Pour les formes pharmaceutiques autorisées présentant des problèmes potentiels d’innocuité des excipients, les directives de l’AEM concernant le sorbitol, le propylène glycol, l’éthanol et le benzoate de sodium ont servi à déterminer si un usage pédiatrique était acceptable.Résultats : Des 56 médicaments étudiés faisant l’objet d’une préparation magistrale, 27 (48 %) avaient une forme pharmaceutique commercialisée adaptée aux enfants en dehors du Canada. Au total, ces médicaments sont sur le marché canadien depuis une médiane de 35 ans et près de la moitié (27 [48 %]) ont une indication pédiatrique au Canada.Conclusions : Le Canada accuse un retard par rapport aux États-Unis et à l’Union européenne quant à la disponibilité et à l’accès à des formes pharmaceutiques adéquates pour les enfants. La petite taille du marché, les incertitudes en matière réglementaire et les lacunes concernant le remboursement pourraient notamment expliquer cet écart. Il est nécessaire de prendre des mesures pour mettre en place des réglementations et des incitatifs ainsi que des politiques de remboursement axés sur les enfants pour répondre à ces besoins criants.Mots-clés : préparation magistrale, médicaments adaptés aux enfants, médicaments pédiatriques pour administration oral

Development of a national neonatal intensive care unit-specific antimicrobial stewardship programme in Canada: protocol for a cohort study

Introduction Early empiric treatment with broad-spectrum antimicrobials is common in neonatal intensive care units (NICU) due to the non-specific clinical presentation of infection. However, excessive and inappropriate antimicrobial use can lead to the emergence of drug-resistant organisms and adverse neonatal outcomes. This study aims to develop and implement a nationwide NICU-specific antimicrobial stewardship programme (ASP) to promote judicious antimicrobial use and control the emergence of multidrug-resistant organisms (MDROs) in Canada.Methods and analysis Our study population will include all very low-birth-weight neonates admitted to participating tertiary NICU in Canada. Based on the existing limited literature, we will develop consensus on NICU antimicrobial stewardship interventions to enhance best practices. Using an expanded Canadian Neonatal Network (CNN) platform, we will collect data on antimicrobial use and the susceptibility of organisms identified in clinical samples from blood and cerebrospinal fluid over a period of 2 years. These data will be used to provide all NICU stakeholders with benchmarked centre-adjusted antimicrobial use and MDRO prevalence reports. An ASP plan will be developed at both individual unit and national levels in the subsequent years. Knowledge translation strategies will be implemented through the well-established Evidence-based Practice for Improving Quality methodology.Ethics and dissemination Ethics for the study has been granted by the University of British Columbia Children’s & Women’s Research Ethics Board (H19-02490) and supported by CNN Executive Committee. The study results will be disseminated through national organisations and open access peer-reviewed publications.Trial registration number NCT04388293

Influencia de la presión de agua y el porcentaje de sólidos en la recuperación de oro mediante concentración gravimétrica centrífuga para un relave tipo óxido procedente de la Provincia de Sánchez Carrión

En esta investigación experimental se estudió un relave de mineral aurífero tipo óxido procedente de la Provincia de Sánchez Carrión, cuya composición química analizada fue de 1.35 g/TM de Au. Estos relaves se encuentran como pasivos ambientales, por lo cual se planteó hacer un tratamiento de gravimetría mediante concentración centrífuga, evaluando la presión de agua a 5, 7 y 9 psi, y el porcentaje de sólidos a 30, 35 y 40%, para luego hacer los balances metalúrgicos para determinar la recuperación y ley de oro en el concentrado. De los resultados obtenidos se determina que a medida que disminuye el porcentaje de sólidos se incrementa la recuperación y ley de oro, en cuanto a la presión de agua se genera una curva convexa obteniéndose la mas alta recuperación de oro de 36.96% con ley de 18,97 g/TM de oro, a 7 psi de presión de agua y 30 % de sólidos. La mas baja recuperación fue de 13.47% de oro a 9 psi y 40% de sólidos. La concentración gravimétrica centrífuga variando la presión de agua y el porcentaje de sólidos influyen en la recuperación de oro para un relave de mineral tipo óxido, obteniendo una ley de oro que permitirá su comercialización y luego hacer una depósito adecuado de dichos relaves. A un 95% de significancia la presión de agua y el porcentaje de sólidos influyen significativamente en la recuperación de oro mas no la interacción que no es significativo, mediante la operación de concentración gravimétrica centrífuga.TesisIn this experimental research was studied a rust - type ore from the Province of Sánchez Carrión, whose chemical composition analyzed was 1.35 g / MT Au. These tailings are found to be environmental passives, for which it was proposed to make gravimetric treatment by centrifugal concentration, evaluating the water pressure at 5, 7 and 9 psi, and the percentage of solids at 30, 35 and 40%, then Make the Metallurgical balances to determine the recovery and gold law in the concentrate. From the results obtained it is determined that the solids percentage decreases the recovery and gold law increase, as for the water pressure, the convex curve is generated, obtaining the highest gold recovery of 36.96% with a law of 18, 97 g / MT Gold, at 7 psi water pressure and 30% solids. The lowest recovery was 13.47% gold at 9 psi and 40% solids. The centrifugal gravimetric concentration varying the water pressure and the percentage of solids influence the recovery of gold for a rust-type ore, obtaining a gold law that will allow its commercialization and then make an adequate deposit of said tailings. At 95% significance, the water pressure and the solids percentage significantly influence the gold recovery, but not the interaction, which is not significant, by means of the centrifugal gravimetric concentration