Neonatal formulations: the need for a tailored, knowledge driven approach

To attain effective and safe pharmacotherapy in neonates, caregivers have to consider both the clinical characteristics of the newborn and the pharmacokinetic estimates of a given compound during prescription and administration. Overall, clearance in neonates is low when compared to other pediatric subpopulations. Despite this overall low clearance, there is already extensive between individual variability in clearance in early life. As a consequence, neonates are in urgent need of tailored drug product development that considers the need for both low and flexible dosing to maintain dose accuracy. During the development of such formulations tailored for neonates, there is also a need for guidance on excipient exposure. The available knowledge on the safety or toxicity of excipients is limited and difficult to retrieve, but there are initiatives (e.g. Safety and Toxicity of Excipients for Pediatrics [STEP] database initiative) to improve the present situation. In addition, population focussed studies on aspects of clinical pharmacology of excipients in neonates should be conducted. The propylene glycol research project and the European Study for Neonatal Excipient Exposure (ESNEE) initiative illustrate its feasibility. Finally, until tailored formulations make it to the market, compounding practices for drug formulations in neonates should be evaluated to guarantee correct dosing, product stability, safety and to support pharmacists in their daily practice.status: publishe

Prospective assessment of short-term propylene glycol tolerance in neonates

Introduction Propylene glycol (PG) is an unintentional frequently administered solvent in neonates despite the fact that PG accumulation potentially results in hyperosmolarity, lactic acidosis and renal/hepatic toxicity. Methods Prospective evaluation of renal (diuresis, creatinaemia, sodium), metabolic (base excess, anion gap, lactate, bicarbonate) and hepatic (alanine transaminase, aspartate aminotransferase, direct bilirubinaemia) tolerance to PG in (pre)term neonates following intravenous administration of formulations (paracetamol, phenobarbital, digoxin) that contain PG. Observations from 48 h before up to 48 after the last PG administration were described and compared (paired analysis). Clinical characteristics and observations collected following intravenous PG-paracetamol administration were compared with a historical cohort of neonates in whom similar (renal, hepatic) observations during exposure to a mannitol-containing paracetamol formulation were collected. Results 5566 observations were collected in 69 neonates before, during and following median PG exposure of 34 mg/kg/24 h (range 14-252). Progressive postnatal adaptation in renal, metabolic and hepatic function was documented, unrelated to the PG exposure. In the subgroup of 40 cases treated with intravenous PG-paracetamol, observations on renal and hepatic function were similar to a historical cohort of published observations following exposure to intravenous mannitol-paracetamol. Conclusions Unintended PG administration (34 mg/kg/24 h) for a maximum of 48 h seems to be tolerated in (pre)term neonates and does not affect short-term postnatal adaptations. Further studies on PG disposition and the level of safe exposure to PG, including long-term safety data in neonates are needed.status: publishe

Voriconazole plasma levels in children are highly variable

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Supplementation of vitamins, trace elements and electrolytes in the PEPaNIC Randomised Controlled Trial:: Composition and preparation of the prescription

Background and aims Following the results of the paediatric early versus late parenteral nutrition in critical illness (PEPaNIC) multicentre, randomised, controlled trial, the new ESPGHAN/ESPEN/ESPR/CSPEN and ESPNIC guidelines recommend to consider withholding parenteral macronutrients for 1 week, while providing micronutrients, in critically ill children if enteral nutrition is insufficient. Critically ill children are suspected to be vulnerable to micronutrient deficiencies due to inadequate enteral nutrition, increased body's demands and excessive losses. Hitherto, micronutrient requirements in PICU are estimated based on recommended daily intakes for healthy children and expert opinion. We aimed to provide an overview of the current practice of micronutrient administration and practical considerations in the three participating centres of the PEPaNIC study, and compare these therapies with the recommendations in the new ESPGHAN/ESPEN/ESPR/CSPEN guidelines. Methods We describe the current composition and preparation of the prescribed parenteral micronutrients (consisting of vitamins, trace elements and electrolytes) in the three centres (Leuven, Rotterdam and Edmonton) that participated in the PEPaNIC RCT, and compare this per micronutrient with the ESPGHAN/ESPEN/ESPR/CSPEN guidelines recommendations. Results The three centres use a different micronutrient supplementation protocol during the first week of critical illness in children, with substantial differences regarding the amounts administered. Leuven administers commercial vitamins, trace elements and electrolytes in separate infusions both in 4 h. Rotterdam provides commercial vitamins and trace elements simultaneously via 8-h infusion and electrolytes continuously over 24 h. Lastly, Edmonton administers commercial vitamins and institutionally prepared trace elements solutions in 1 h and electrolytes on demand. Comparison with the ESPGHAN/ESPEN/ESPR/CSPEN guidelines yields in differences between the recommendations and the administered amounts, which are most substantial for vitamins. Conclusion The practice of intravenous micronutrient administration differs substantially between the three PEPaNIC centres and in comparison with the current guideline recommendations. This deviation is at least partially explained by the inability to provide all recommended amounts with the currently available commercial products and by the lack of strong evidence supporting these recommendations