Comparing paediatric intravenous phenytoin doses using physiologically based pharmacokinetic (PBPK) modelling software

AbstractPurposeTo use a physiologically based pharmacokinetic (PBPK) modelling system to predict the serum levels achieved by two different intravenous loading doses of phenytoin.MethodsA phenytoin pharmacokinetic model was used in the Simcyp™ population-based ADME simulator, simulating 100 children age 2–10 years receiving intravenous phenytoin (18 and 20mg/kg). Visual checks were used to evaluate the predictive performance of the candidate model.ResultsLoading with doses of 18mg/kg, blood levels were sub-therapeutic in 22/100 (concentration at 2h post infusion (C2h) <10μg/mL), therapeutic in 62/100 (C2h 10–20μg/mL), and supra-therapeutic in 16/100 (C2h>20μg/mL). Loading with 20mg/kg, the percentages were 15, 59, and 26, respectively. Increasing from 18 to 20mg/kg increased the mean C2h from 16.0 to 17.9μg/mL, and the mean AUC from 145 to 162μg/mL/h. A C2h>30μg/mL was predicted in 4% and 8% of children in the 18 and 20mg/kg doses, with 3% predicted to have a C2h>40μg/mL following either dose. For maintenance doses, a 1st dose of 2.5 or 5mg/kg (intravenous) given at 12h (after either 18 or 20mg/kg loading) gives the highest percentages of 10–20μg/mL serum concentrations. For sub-therapeutic concentrations following intravenous loading (20mg/kg), a 1st maintenance dose (intravenous) of 10mg/kg will achieve therapeutic concentrations in 93%.ConclusionUse of PBPK modelling suggests that children receiving the 20mg/kg intravenous loading dose are at slightly increased risk of supra-therapeutic blood levels. Ideally, therapeutic drug monitoring is required to monitor serum concentrations, although the dose regime suggested by the BNFc appear appropriate

Prioritising neonatal medicines research: UK Medicines for Children Research Network scoping survey

BACKGROUND: The dosing regimen and indications for many medicines in current use in neonatology are not well defined. There is a need to prioritise research in this area, but currently there is little information about which drugs are used in UK neonatal units and the research needs in this area as perceived by UK neonatologists. METHODS: The Neonatal Clinical Studies Group (CSG) of the Medicines for Children Research Network (MCRN) undertook a 2 week prospective scoping survey study to establish which medicines are used in UK neonatal units; how many babies are receiving them; and what clinicians (and other health professionals) believe are important issues for future research. RESULTS: 49 out of 116 units responded to at least one element of the survey (42%). 37 units reported the number of neonates who received medicines over a 2 week period. A total of 3924 medicine-patient pairs were reported with 119 different medicines. 70% of medicine-patient pairs involved medicines that were missing either a license or dose for either term or preterm neonates. 4.3% of medicine-patient pairs involved medicines that were missing both license and dose for any neonate. The most common therapeutic gap in need of additional research identified by UK neonatologists was chronic lung disease (21 responding units), followed by patent ductus arteriosus and vitamin supplements (11 responding units for both) CONCLUSION: The research agenda for neonatal medicines can be informed by knowledge of current medicine use and the collective views of the neonatal community

What causes poverty and how does this contribute to respiratory inequality?

Poverty at an individual level is experienced when individuals or households cannot access sufficient resources to meet their needs and participate in wider society. At a societal level, poverty can be understood as either absolute on a global scale, or relative to the society or country. Countries with higher levels of relative poverty are more likely to have worse health outcomes than countries with better social equality. Those living in poverty are priced out of healthy living and face barriers to accessing healthcare, and exposures directly related to poverty work synergistically to change an individual's physiology. Respiratory health is particularly influenced by these mechanisms: Living in poverty causes respiratory disease by limiting material and societal resources for good health, and through increased exposures to risk factors. These same risk factors that cause respiratory disease also cause worse respiratory disease outcomes including morbidity and mortality

Update and harmonisation of guidance for the management of diabetic ketoacidosis in children and young people in the UK

Diabetic ketoacidosis (DKA) is a life-threatening complication of type 1 diabetes mellitus. Careful and timely intervention is required to optimise glycaemic control and reduce the risk of mortality and devastating complications. Of these, cerebral oedema is the leading cause of death, with a mortality rate of approximately 25%. This article highlights the recent updates to UK fluid therapy guidelines for DKA and provides clinical context for the benefit of paediatricians and junior doctors in light of this new guidance

Platelet-derived growth factor D expression in adrenal cells is modulated by corticosteroids: putative role in adrenal suppression

BACKGROUND: Adrenal suppression is a clinically concerning side effect of inhaled corticosteroid (ICS) treatment in patients with asthma. Increased susceptibility to ICS-induced adrenal suppression has previously been identified in those with the rs591118 polymorphism in platelet-derived growth factor D (PDGFD). The mechanism underpinning this relationship is not known. METHODS: H295R cells were genotyped for rs591118 using a validated Taqman PCR allelic discrimination assay. H295R cell viability was determined after treatment with beclometasone and fluticasone (range 0–330 μM). Cortisol was measured in cell culture medium using competitive enzyme immunoassay. RESULTS: PDGFD protein expression in H295R cells was confirmed using Western blotting. When ACTH and forskolin were added to H295R cells, a reduction in PDGFD expression was seen, which was then restored by incubation with prochloraz, a known inhibitor of steroidogenesis. A dose-dependent, decrease in PDGFD expression was observed with beclometasone (over a 24 h incubation period) but not with beclometasone incubations beyond 24 h nor with fluticasone (at 24 or 48 h). CONCLUSIONS: H295R cells express PDGFD protein, which can be modulated by incubation with steroidogenesis agonists and antagonists and additionally with exogenous beclometasone. IMPACT: PDGFD is expressed in the human adrenal cell line, H295R, and expression can be modulated by beclometasone as well as agonists/antagonists of steroidogenesis. This builds on previous research that identified a SNP in PDGFD (rs591118) as an independent risk factor for adrenal suppression in adults and children with obstructive airway disease treated with inhaled corticosteroids. First in vitro experiments to support a link between the PDGF and cortisol production pathways, supporting the hypothesis that PDGFD variants can affect an individual’s sensitivity to corticosteroid-induced adrenal suppression

Antenatal determinants of child lung development

There are several important antenatal factors including maternal stress, tobacco smoking, air pollution and nutrition that have been shown to influence lung development in utero and beyond. Exposure to these is associated with detrimental lung function and respiratory morbidity in childhood that can persist into adulthood. Environmental factors in utero may influence adult disease, referred to as fetal programming. This chapter reviews the proposed underlying mechanisms behind the effect on lung development including neurohormonal, immune, inflammatory and epigenetic pathways. There is a significant impact of sociodemographic inequalities on each of these antenatal determinants of child lung development, even in countries with a universally free healthcare system. As such, it is important that we do not refer to these simply as "lifestyle choices of expectant mothers", but rather aim to tackle these inequalities and provide equitable antenatal care and education to women in pregnancy to improve lifelong respiratory health