Inappropriate oral formulations and information in paediatric trials

Previously, quality of formulations information provided for oral medications used in paediatric clinical trials published in 10 highly cited journals between 2002 and 2004 raised concerns. This short report explores if there was any subsequent improvement on how the formulations used in trials involving children

Medicines management across the primary-hospital healthcare interface: a study of paediatric patients

A comparison of medicines management documents in use by NHS organisations in the West Midlands confirms that there are important differences between the primary care and hospital sectors in respect to medicines management interface issues. Of these, two aspects important to paediatric patients have been studied. These are the transfer of information as a patient is admitted to hospital, and access to long-term medicines for home-patients. National guidance provided by NICE requires medication reconciliation to be undertaken on admission to hospital for adults. A study of paediatric admissions, reported in this thesis, demonstrates that the clinical importance of this process is at least as important for children as for adults, and challenges current UK guidance. The transfer of essential medication information on hospital admission is central to the medication reconciliation process. Two surveys of PCTs in 2007 and again in 2009 demonstrate that very few PCTs provide guidance to GPs to support this process. Provision of guidance is increasing slowly but remains the exception. The provision of long-term medicines for children at home is hindered by this patient population often needing unlicensed drugs. Further studies demonstrate that primary care processes regularly fail to maintain access to essential drugs and patients and their carers frequently turn to hospitals for help. Surveys of hospital medical staff (single site) and hospital nurses (six UK sites) demonstrates the activity these healthcare workers perform to help children get the medicines they need. A similar survey of why carers turn to a hospital pharmacy department for urgent supplies (usually termed rescue-medicines) adds to the understanding of these problems and supports identifying service changes. A large survey of community pharmacies demonstrates the difficulties they have when dispensing hospital prescriptions and identifies practical solutions. This programme concludes by recommending service changes to support medication management for children.

Sedation in paediatric intensive care

Paediatric intensive care is an expanding specialty that has been shown to improve the quality of care provided to critically ill children. An important aspect of the management of critically ill children includes the provision of effective sedation to reduce stress and anxiety during their stay in intensive care. However, to achieve effective and safe sedation in these children, is recognised as a challenge that is not without risk. Often children receive too much or too little sedation resulting in over sedation or under sedation respectively. These problems have arisen owing to a lack of information regarding altered pharmacokinetics and pharmacodynamics of medicines administered to critically ill children. In addition there are few validated sedation scoring systems in practice with which to monitor level of sedation and titrate medication appropriately. This study consisted of two stages. Stage 1 investigated the reproducibility and practicality of two observational sedation assessment scales for use in critically ill children. The two scales were different in design, the first being simple in design requiring a single assessment of the patient. The second was more complex in design requiring assessment of five patient parameters to obtain an overall sedation score. Both scales were found to achieve good reproducibility (kappa values 0.50 and 0.62 respectively). Practicality of each sedation scale was undertaken by obtaining nursing staff opinion about both scales using questionnaire and interview technique. It was established that nursing staff preferred the second, more complex sedation scale mainly because it was perceived to give a more accurate assessment of level of sedation and anxiety rather than merely level of sedation. Stage 2 investigated the pharmacokinetics and pharmacodynamics of midazolam in critically ill children. 52 children, aged between 0 and 18 years were recruited to the study and 303 blood samples taken to analyse midazolam and its metabolites, I-hydroxyrnidazolam (I-OR) and 4-hydroxymidazolam (4-0H). Analysis of plasma was undertaken using high performance liquid chromatography. A significant correlation was found between midazolam plasma concentration and sedative effect (r=0.598, p=O.OI). It was found that a midazolam plasma concentration of 223ng/ml (±31.9) achieved a satisfactory level of sedation. Only a poor correlation was found between dose of midazolam and plasma concentration of midazolam. Similarly only a poor correlation was found between sedative effect and dose of midazolam. Clearance of midazolam was found to be 6.3mllkglmin (±0.36), which is lower than that reported in healthy children (9.Il-13.3mllkg/min). Age related differences in midazolam clearance were observed in the study. Neonates produced the lowest clearance values (l.63mllkg/min), compared to children aged 1 to 12 months (8.52mllkg/min) who achieved the highest clearance values. Clearance was found to decrease after the age of 12 months to values of 5.34mllkglmin in children aged 7 years and above. Patients with renal (n=5) and liver impairment (n~4) were found to have reduced midazolam clearance (1.37 and 0.74ml/kg/min respectively). Plasma concentrations of I-OH and 4-0H ranged from 0-5 1 89nglml and 0-27 Inglml respectively. All children were found to be capable of producing both metabolites irrespective of age, although no trend was established between age and extent of production of either metabolite. Disease state was found to affect production of l-OH. Patients with renal impairment (n=5) produced the lowest I-OH midazolam plasma ratio (0.059) compared to patients with head injury (0.858). Patients with severe liver impairment were found to be capable of manufacturing both metabolites despite having a severely damaged liver.

Paediatric 'care closer to home':stake-holder views and barriers to implementation

In this study we explore the views of NHS stakeholders on providing paediatric ‘care closer to home’ (CCTH), in community-based outpatient clinics delivered by consultants. Design: Semi-structured interviews and thematic framework analysis. Setting: UK specialist children's hospital and surrounding primary care trusts. Participants: 37 NHS stakeholders including healthcare professionals, managers, commissioners and executive team members. Results: Participants acknowledged that outreach clinics would involve a change in traditional ways of working and that the physical setting of the clinic would influence aspects of professional practice. Different models of CCTH were discussed, as were alternatives for improving access to specialist care. Participants supported CCTH as a good principle for paediatric outpatient services; however the challenges of setting up and maintaining community clinics meant they questioned how far it could be achieved in practice. Conclusions: The place of service delivery is both an issue of physical location and professional identity. Policy initiatives which ignore assumptions about place, power and identity are likely to meet with limited success.

Validation of the Paediatric food allergy quality of life questionnaire (PFA-QL)

Objective - The aim of the current study was to validate child (PFA-QL) and parent–proxy (PFA-QL-PF) versions of the scale in a specialist allergy clinic and in parents of children with food allergy. Methods - For the clinic sample, a generic QoL scale (PedsQL) and the PFA-QL were completed by 103 children (age 6–16 yrs) with peanut or tree nut allergy; test–retest reliability of the PFA-QL was tested in 50 stable patients. For the non-clinical sample, 756 parents of food allergic children completed the PFA-QL-PF, the Child Health Questionnaire (CHQ-PF50), Food Allergy Quality of Life Parental Burden Scale (FAQL-PB) and a Food Allergy Impact Measure. Results - The PFA-QL and PFA-QL-PF had good internal consistency (a's of 0.77–0.82), and there was moderate-to-good agreement between the generic- and disease-specific questionnaires. The PFA-QL was stable over time in the clinic sample, and in both samples, girls were reported to have poorer QoL than boys. Conclusions - The PFA-QL and PFA-QL-PF are reliable and valid scales for use in both clinical and non-clinical populations. Unlike other available tools, they were developed and validated in the UK and thus provide a culture-specific choice for research, clinical trials and clinical practice in the UK. Validation in other countries is now needed.

Health care professionals' views of paediatric outpatient non-attendance:implications for general practice

Background. Non-attendance at paediatric hospital outpatient appointments poses potential risks to children's health and welfare. Prevention and management of missed appointments depends on the perceptions of clinicians and decision makers from both primary and secondary care, including general practitioners (GPs) who are integral to non-attendance follow-up. Objectives. To examine the views of clinical, managerial and executive health care staff regarding occurrence and management of non-attendance at general paediatric outpatient clinics. Methods. A qualitative study using individual semi-structured interviews was carried out at three English Primary Care Trusts and a nearby children's hospital. Interviews were conducted with 37 staff, including GPs, hospital doctors, other health care professionals, managers, executives and commissioners. Participants were recruited through purposive and 'snowball' sampling methods. Data were analysed following a thematic framework approach. Results. GPs focused on situational difficulties for families, while hospital-based staff emphasized the influence of parents' beliefs on attendance. Managers, executives and commissioners presented a broad overview of both factors, but with less detailed views. All groups discussed sociodemographic factors, with non-attendance thought to be more likely in 'chaotic families'. Hospital interviewees emphasized child protection issues and the need for thorough follow-up of missed appointments. However, GPs were reluctant to interfere with parental responsibilities. Conclusion. Parental motivation and practical and social barriers should be considered. Responsibilities regarding missed appointments are not clear across health care sectors, but GPs are uniquely placed to address non-attendance issues and are central to child safeguarding. Primary care policies and strategies could be introduced to reduce non-attendance and ensure children receive the care they require. © The Author 2013.

The cost of paediatric obesity

There has been a great deal of media attention given to the rising levels of obesity and overweight in children and adolescents, but what is the real cost of pediatric obesity? This article reviews information about the recent rise in pediatric obesity and discusses the cost of this condition from medical, financial and psychological perspectives.

Ethanol intake of paediatric intensive care patients

Background - Limiting the amount of alcohol in children's medicines is advisable but as alcohol is the second most common solvent used in liquid preparations, paediatric patients with increased medication intake may be exposed to a considerable alcohol intake. Few medicines are specifically designed for children in Paediatric Intensive Care (PICU), and therefore adult formulations are frequently administered, with high medication use further exposing a PICU patient to undesired alcohol intake. Aims - This small pilot study aimed to examiine the intake of a sample of PICU patients, highlight common medicines used on PICU containing alcohol, provide alternatives where possible and where alternatives are not possible, provide the prescriber with a list of the higher alcohol containing medicines. Method - A retrospective medication chart review was undertaken as a two point snap shot. Data collected included age, weight, medications prescribed and the formulations used at time of the study. The patients' sedation score was recorded. The electronic medicine compendium (EMC) was consulted for any ethanol content for the commercially available products. The manufacturer was contacted for ethanol content of all ‘specials’ and any commercial products found to contain ethanol from the EMC. The PICU patient's daily intake of ethanol was calculated. The calculation was converted to an adult equivalent alcohol unit intake and although this method of conversion is crude and does not take physiological differences of adult and children into account, it was done in order to provide the clinician with commonly used terminology in deciding the risk to the patient. Results - Twenty-eight patients were prescribed a range of 69 different medications. Of the 69 medicines, 12 products were found to contain ethanol. Patient ages ranged from a 26 week premature infant to 15 years old, weights ranges from 0.7 kg to 45 kg. Only 2 out of the 28 patients did not receive ethanol containing medications, and most patients were prescribed at least two medicines containing ethanol. Daily ethanol intake uncorrected for weight ranged from 0.006 ml to 2.18 ml (median 0.26 ml). Converting this to adult units per week, alcohol intake ranged from 0.07 to 15.2 units (median 1.4 units). The two patients receiving above 15 units/week adult equivalent were prescribed an oral morphine weaning regimen, therefore the high alcohol exposure was short term. The most common drugs prescribed containing alcohol were found to be nystatin, ranitidine, furosemide and morphine. No commercially available alcohol-free oral liquid preparations were found for ranitidine, furosemide or morphine at the time of the study. Correlation of the sedation score against ethanol intake was difficult to analyse as most patients were actively sedated. Conclusions - Polypharmacy in PICU patients increases the exposure to alcohol. Some commercially available medicines provide excessive ethanol intake, providing the clinician with ethical, potentially economical dilemmas of prescribing an unlicensed medicine to minimise ethanol exposure. Further research is required to evaluate the scope of the problem, effects of exposure and provision of alcohol free formulations.

Population pharmacokinetic and pharmacogenetic analysis of tacrolimus in paediatric liver transplant patients

Aims - To build a population pharmacokinetic model that describes the apparent clearance of tacrolimus and the potential demographic, clinical and genetically controlled factors that could lead to inter-patient pharmacokinetic variability within children following liver transplantation. Methods - The present study retrospectively examined tacrolimus whole blood pre-dose concentrations (n = 628) of 43 children during their first year post-liver transplantation. Population pharmacokinetic analysis was performed using the non-linear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance and influential covariates. Results - The final model identified time post-transplantation and CYP3A5*1 allele as influential covariates on tacrolimus apparent clearance according to the following equation: TVCL = 12.9 x (Weight/13.2)0.35 x EXP (-0.0058 x TPT) x EXP (0.428 x CYP3A5) where TVCL is the typical value for apparent clearance, TPT is time post-transplantation in days and the CYP3A5 is 1 where *1 allele is present and 0 otherwise. The population estimate and inter-individual variability (%CV) of tacrolimus apparent clearance were found to be 0.977 l h−1 kg−1 (95% CI 0.958, 0.996) and 40.0%, respectively, while the residual variability between the observed and predicted concentrations was 35.4%. Conclusion Tacrolimus apparent clearance was influenced by time post-transplantation and CYP3A5 genotypes. The results of this study, once confirmed by a large scale prospective study, can be used in conjunction with therapeutic drug monitoring to recommend tacrolimus dose adjustments that take into account not only body weight but also genetic and time-related changes in tacrolimus clearance.

Population pharmacokinetic and pharmacogenetic analysis of 6-mercaptopurine in paediatric patients with acute lymphoblastic leukaemia

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The cytotoxic effects of 6-mercaptopurine (6-MP) were found to be due to drug-derived intracellular metabolites (mainly 6-thioguanine nucleotides and to some extent 6-methylmercaptopurine nucleotides) rather than the drug itself. • Current empirical dosing methods for oral 6-MP result in highly variable drug and metabolite concentrations and hence variability in treatment outcome. WHAT THIS STUDY ADDS • The first population pharmacokinetic model has been developed for 6-MP active metabolites in paediatric patients with acute lymphoblastic leukaemia and the potential demographic and genetically controlled factors that could lead to interpatient pharmacokinetic variability among this population have been assessed. • The model shows a large reduction in interindividual variability of pharmacokinetic parameters when body surface area and thiopurine methyltransferase polymorphism are incorporated into the model as covariates. • The developed model offers a more rational dosing approach for 6-MP than the traditional empirical method (based on body surface area) through combining it with pharmacogenetically guided dosing based on thiopurine methyltransferase genotype. AIMS - To investigate the population pharmacokinetics of 6-mercaptopurine (6-MP) active metabolites in paediatric patients with acute lymphoblastic leukaemia (ALL) and examine the effects of various genetic polymorphisms on the disposition of these metabolites. METHODS - Data were collected prospectively from 19 paediatric patients with ALL (n = 75 samples, 150 concentrations) who received 6-MP maintenance chemotherapy (titrated to a target dose of 75 mg m−2 day−1). All patients were genotyped for polymorphisms in three enzymes involved in 6-MP metabolism. Population pharmacokinetic analysis was performed with the nonlinear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance for the active metabolites. RESULTS - The developed model revealed considerable interindividual variability (IIV) in the clearance of 6-MP active metabolites [6-thioguanine nucleotides (6-TGNs) and 6-methylmercaptopurine nucleotides (6-mMPNs)]. Body surface area explained a significant part of 6-TGNs clearance IIV when incorporated in the model (IIV reduced from 69.9 to 29.3%). The most influential covariate examined, however, was thiopurine methyltransferase (TPMT) genotype, which resulted in the greatest reduction in the model's objective function (P < 0.005) when incorporated as a covariate affecting the fractional metabolic transformation of 6-MP into 6-TGNs. The other genetic covariates tested were not statistically significant and therefore were not included in the final model. CONCLUSIONS - The developed pharmacokinetic model (if successful at external validation) would offer a more rational dosing approach for 6-MP than the traditional empirical method since it combines the current practice of using body surface area in 6-MP dosing with a pharmacogenetically guided dosing based on TPMT genotype.

Population pharmacokinetic model of canrenone after intravenous administration of potassium canrenoate to paediatric patients

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Little is known about the pharmacokinetics of potassium canrenoate/canrenone in paediatric patients WHAT THIS STUDY ADDS • A population pharmacokinetic model has been developed to evaluate the pharmacokinetics of canrenone in paediatric patients who received potassium canrenoate as part of their therapy in the intensive care unit. AIMS To characterize the population pharmacokinetics of canrenone following administration of potassium canrenoate to paediatric patients. METHODS Data were collected prospectively from 23 paediatric patients (2 days to 10 years of age; median weight 4 kg, range 2.16–28.0 kg) who received intravenous potassium canrenoate (K-canrenoate) as part of their intensive care therapy for removal of retained fluids, e.g. in pulmonary oedema due to chronic lung disease and for the management of congestive heart failure. Plasma samples were analyzed by HPLC for determination of canrenone (the major metabolite and pharmacologically active moiety) and the data subjected to pharmacokinetic analysis using NONMEM. RESULTS A one compartment model best described the data. The only significant covariate was weight (WT). The final population models for canrenone clearance (CL/F) and volume of distribution (V/F) were CL/F (l h−1) = 11.4 × (WT/70.0)0.75 and V/F (l) = 374.2 × (WT/70) where WT is in kg. The values of CL/F and V/F in a 4 kg child would be 1.33 l h−1 and 21.4 l, respectively, resulting in an elimination half-life of 11.2 h. CONCLUSIONS The range of estimated CL/F in the study population was 0.67–7.38 l h−1. The data suggest that adjustment of K-canrenoate dosage according to body weight is appropriate in paediatric patients.

Development of an enantiomer selective microsampling assay for the quantification of ketorolac suitable for paediatric pharmacokinetic studies

Background: Ketorolac, a potent nonsteroidal anti-inflammatory drug used for pain control in children, exists as a racemate of inactive R (+) and active S (-) enantiomers. Aim: To develop a microsampling assay for the enantioselective analysis of ketorolac in children. Methods: Ketorolac enantiomers were extracted from 50 µl of plasma by liquid–liquid extraction and separated on a ChiralPak AD-RH. Detection was by a TSQ quantum triple quadrupole mass spectrometer with an electrospray ionisation source operating in a positive ion mode. Five children (age 13.8 (1.6) years, weight 52.7 (7.2) kg), were administered intravenous ketorolac 0.5 mg/kg (maximum 10 mg) and blood samples were taken at 0, 0.25, 0.5, 1, 2, 4, 6, 8 and 12 h post administration. CL, VD and t1/2 were calculated based on non-compartmental methods. Results: The standard curves for R (+) and S (-) ketorolac were linear in the range 0–2000 ng/ml. The LLOQs of the method were 0.15 ng on column and 0.31 ng on column for R (+) and S (-) ketorolac, respectively. The median (range) VD and CL of R (+) and S (-) ketorolac were 0.12 l/kg (0.07–0.17), 0.017 l/h/kg (0.12–0.29) and 0.17 (0.09–0.31) l/kg, 0.049 (0.02–0.1) l/h/kg, p = 0.043), respectively. The median (range) elimination half-life (t1/2) of the R (+) and S (-) ketorolac was 5.0 h (2.5–5.8) and 3.1 h (1.8–4.4), p = 0.043), respectively. Conclusion: The development of a simple, rapid and reliable ketorolac assay suitable for paediatric PK studies is reported. Copyright © 2013 John Wiley & Sons, Ltd.

Potassium canrenoate treatment in paediatric patients:a population pharmacokinetic study using novel dried blood spot sampling

Objective: To characterize the population pharmacokinetics of canrenone following administration of potassium canrenoate (K-canrenoate) in paediatric patients. Methods: Data were collected prospectively from 37 paediatric patients (median weight 2.9 kg, age range 2 days–0.85 years) who received intravenous K-canrenoate for management of retained fluids, for example in heart failure and chronic lung disease. Dried blood spot (DBS) samples (n = 213) from these were analysed for canrenone content and the data subjected to pharmacokinetic analysis using nonlinear mixed-effects modelling. Another group of patients (n = 16) who had 71 matching plasma and DBS samples was analysed separately to compare canrenone pharmacokinetic parameters obtained using the two different matrices. Results: A one-compartment model best described the DBS data. Significant covariates were weight, postmenstrual age (PMA) and gestational age. The final population models for canrenone clearance (CL/F) and volume of distribution (V/F) in DBS were CL/F (l/h) = 12.86 ×  (WT/70.0)0.75 × e [0.066 ×  (PMA - 40]) and V/F (l) = 603.30 ×  (WT/70) × (GA/40)1.89 where weight is in kilograms. The corresponding values of CL/F and V/F in a patient with a median weight of 2.9 kg are 1.11 l/h and 20.48 l, respectively. Estimated half-life of canrenone based on DBS concentrations was similar to that based on matched plasma concentrations (19.99 and 19.37 h, respectively, in 70 kg patient). Conclusion: The range of estimated CL/F in DBS for the study population was 0.12–9.62 l/h; hence, bodyweight-based dosage adjustment of K-canrenoate appears necessary. However, a dosing scheme that takes into consideration both weight and age (PMA/gestational age) of paediatric patients seems more appropriate.

Children's views on unlicensed/off-label paediatric prescribing and paediatric clinical trials

Objectives - To explore the views and perspectives of children on the unlicensed/off-label use of medicines in children and on the participation of children in clinical trials. Methods - Focus-group discussions, involving school children, were carried out in a range of primary and secondary schools in Northern Ireland. A purposeful sample was chosen to facilitate representation of various socioeconomic groupings. Results - A total of 123 pupils, aged from 10 to 16 years, from six schools, participated in 16 focus groups. In general, pupils viewed the unlicensed/off-label use of medicines in children as unsafe and unethical and felt it is necessary to test medicines in children to improve the availability of licensed products. The majority felt that older children should be told, and that parents should be told, about the unlicensed/off-label use of medicines in children, yet they recognised some implications of this, such as potential medication non-adherence. Conclusions - This is the first study to explore the views of healthy children on unlicensed medicine use in children. Children were able to recognise potential risks associated with the unlicensed use of medicines and felt it is necessary to test and license more medicines in children. Practice implications - Health care professionals should consider the views of children in decisions that affect their health.