Minitablets may be an acceptable alternative to liquid in infants and young children

Klingmann V, Linderskamp H, Meissner T, Mayatepek E, Moeltner A, Breitkreutz J, et al. Acceptability of Multiple Uncoated Minitablets in Infants and Toddlers: A Randomized Controlled Trial. J Pediatr 2018;201:202-7. Question Among infants and toddlers/young children, how do minitablet placebos compare with liquid placebos, in acceptability and swallowability

Influence of food on paediatric gastrointestinal drug absorption following oral administration: a review

The objective of this paper was to review existing information regarding food effects on drug absorption within paediatric populations. Mechanisms that underpin food–drug interactions were examined to consider potential differences between adult and paediatric populations, to provide insights into how this may alter the pharmacokinetic profile in a child. Relevant literature was searched to retrieve information on food–drug interaction studies undertaken on: (i) paediatric oral drug formulations; and (ii) within paediatric populations. The applicability of existing methodology to predict food effects in adult populations was evaluated with respect to paediatric populations where clinical data was available. Several differences in physiology, anatomy and the composition of food consumed within a paediatric population are likely to lead to food–drug interactions that cannot be predicted based on adult studies. Existing methods to predict food effects cannot be directly extrapolated to allow predictions within paediatric populations. Development of systematic methods and guidelines is needed to address the general lack of information on examining food–drug interactions within paediatric populations

Determination of healthcare resource and cost implications of using alternative sodium valproate formulations in the treatment of epilepsy in children in England : a retrospective database review

Objectives: The aim of this study was to compare the adherence, healthcare resource and cost implications of using Episenta® minitablets or Epilim® monolithic tablet in the treatment of epilepsy in children in England. Design: This is a retrospective analysis of healthcare administrative databases. Setting: The study analysed data collected from Primary Care (Clinical Practice Research Datalink (CPRD)) and Secondary Care (Hospital Episode Statistics (HES)) in England, UK. Participants: Patients (stratified by age 0–12; 0–17 and 18+ years) with a diagnosis of epilepsy in receipt of a new prescription for Episenta® minitablets or Epilim® monolithic tablet from January 2012 to October 2017. Limited to those with a minimum of 12 months follow-up. Main outcome measures: Determining the impact of sodium valproate formulation on measures of treatment adherence and healthcare resource usage. Results: There were 793 patients in the dataset: 84 on Episenta® minitablets and 709 on Epilim® tablets. Measures of medication adherence were not significantly different between the minitablet formulation and the monolithic matrix tablet. However there was a greater annualised incidence rate of epilepsy related primary healthcare contacts in a paediatric population from the tablet formulation compared to those treated with minitablets (95% CI [−1.561,0.0152]) for those aged 0–12 and (95% CI [−1.3234,−0.0058]) for those aged 0–17. This is found despite a lower dose being used in the minitablet cohort (595 mg vs 945 mg for the tablet) for those aged 0–17 which indicates effective therapy at a lower dose using the minitablet compared to the monolithic tablet formulation. Conclusions: Minitablet formulations of sodium valproate (presented as granules in capsules or sachets) can provide better therapeutic outcomes and reduced associated healthcare resource costs compared to monolithic tablets in children and young people with epilepsy. The interpretation of this data is limited by the large difference in sample size between the two groups which needs additional investigation to generate matched data for future comparisons. Further work is required to understand why the Episenta® minitablets formulation generated better outcomes in paediatric populations

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

Pharmacy and formulation support for paediatric clinical trials in England

Availability and sourcing of investigational drugs for paediatric clinical trials is known to be a challenge for investigator-led clinical trials. The National Institute of Health Research Clinical Research Network: Children (CRN: Children) provides support for formulations and pharmacy related issues to researchers planning and setting up paediatric clinical trials within England. This paper reviews pharmacy and formulation support provided to a consecutive series of investigator-led clinical studies supported by CRN:Children. Case studies are included to describe some of the unique pharmaceutical challenges encountered. 44 trials were reviewed and a total of 103 products were required to support these clinical trials. UK authorised products were suitable for use for 62 of these 103 products. In the remaining 41 cases, 4 could be sourced as an authorised product within the European Union and the remaining 37 required bespoke manufacture. Bespoke manufacture of an investigational drug or placebo is costly. Typical costs for the initial development and testing of a bespoke investigational drug or placebo were in the range of £30,000–100,000 per product. The estimated cost for 19 out of 45 trials was available; in summary, the costs on a per patient per day of therapy basis ranged from under £1 to almost £600; short studies involving multiple agents are obviously the most expensive. This range is dependent upon the need for bespoke manufacture and also the number of participants within the trial. The arrangements for investigational drug supply can greatly affect the study design, regulatory requirements, trial logistics, as well as the total cost of research. As investigational product related activities are often costly, necessitating months of advance planning, it is imperative that specialist inputs are sought from the very start of the study design and planning process

In vitro models to evaluate ingestible devices:present status and current trends

Orally ingestible medical devices offer significant opportunity in the diagnosis and treatment of gastrointestinal conditions. Their development necessitates the use of models that simulate the gastrointestinal environment on both a macro and micro scale. An evolution in scientific technology has enabled a wide range of in vitro, ex vivo and in vivo models to be developed that replicate the gastrointestinal tract. This review describes the landscape of the existing range of in vitro tools that are available to characterize ingestible devices. Models are presented with details on their benefits and limitations with regards to the evaluation of ingestible devices and examples of their use in the evaluation of such devices is presented where available. The multitude of models available provides a suite of tools that can be used in the evaluation of ingestible devices that should be selected on the functionality of the device and the mechanism of its function

The application of tribology in assessing texture perception of oral liquid medicines

The palatability of medicines is likely to have a significant impact on patient adherence and consequently, on the safety and efficacy of a medicinal product. Palatability encompasses properties of medicines not limited to taste including swallowability (e.g. size, shape, texture). However, there has been limited work undertaken to measure the texture of medicines and how this may affect palatability and subsequent adherence. Tribology offers an understanding of oral processes and can allow physical properties of materials to be linked to "mouthfeel". This paper describes a preliminary application of tribology to oral liquid medicines and demonstrates that this technique is useful in the development of future oral liquid medicines

Dissolution profile of theophylline modified release tablets, using a biorelevant Dynamic Colon Model (DCM)

AbstractThe human proximal colon has been considered a favourable site to deliver drugs for local and systemic treatments. However, modified dosage forms face a complex and dynamically changing colonic environment. Therefore, it has been realized that in addition to the use of biorelevant media, the hydrodynamics also need to be reproduced to create a powerful in vitro dissolution model to enable in vivo performance of the dosage forms to be predicted.A novel biorelevant Dynamic Colon Model (DCM) has been developed which provides a realistic environment in terms of the architecture of the smooth muscle, the physical pressures and the motility patterns occurring in the proximal human colon. Measurements of pressure inside the DCM tube confirmed a direct association between the magnitude of the pressure signal with the occlusion rate of the membrane and the viscosity of the fluid.The dissolution profile and the distribution of the highly soluble drug, theophylline, were assessed by collecting samples at different locations along the DCM tube. Differences in the release rates of the drug were observed which were affected by the sampling point location, the viscosity of the fluid and the mixing within the DCM tube. Images of the overall convective motion of the fluid inside the DCM tube obtained using Positron Emission Tomography enabled relation of the distribution of the tracer to likely areas of high and low concentrations of the theophylline drug.This information provides improved understanding of how extensive phenomena such as supersaturation and precipitation of the drug may be during the passage of the dosage form through the proximal colon

Use of PLIF to assess the mixing performance of small volume USP 2 apparatus in shear thinning media

AbstractPlanar Laser Induced Fluorescence (PLIF) was used to assess mixing in small volume USP 2 dissolution apparatus for a range of viscous fluids which mimic gastrointestinal media, especially in the fed state. The release into the media from a specially prepared tablet containing Rhodamine 6G dye was tracked in time and the areal distribution method developed by Alberini et al. (2014a) was implemented to characterise the mixing performance. The distributions of the individual striations for selected mixing levels were also presented. These findings illustrate the poor mixing performance of the apparatus resulting in high variance of the dissolution data when working with viscous media. Analysis of data using CoV gives misleading results for the mixing performance of the small volume USP 2 dissolution apparatus. The results showed that the best mixing was mainly located above the blade and close to the wall, i.e. in the region where intensive motion takes place. This work presents important guidelines and precautions for choosing the proper sampling point for a wide range of liquid viscosities to minimize the variability of the dissolution data