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IntroductionLabeledpediatric indications for prescription of fluoroquinolones (FQ) are limited. Furthermore, the safety of systemic FQ for growing children has been debated for a long time.1,2 Nevertheless, prescribing FQ for children can be advantageous. First, FQ cover a broad spectrum of bacteriae.3 Second, pharmacokinetic (PK) characteristics of systemic FQ are favourable. The bioavailability of common FQ agents is usually high and FQ typically penetrate in deep compartments.4,5 In this retrospective multicenter drug utilisation study, we aimed to investigate indications for FQ prescription in a population of children hospitalised in two Belgian university children’s hospitals. Additionally, another goal was to assess the adequacy of prescribed doses, and risk factors for incorrectly dosed FQ prescriptions within our population.MethodsUsing data obtained from electronic medical files, the study included all children who received a sys-temic FQ prescription in two Belgian university children’s hospitals between 2010–2013. Two authors reviewed pre-scribed daily doses. Univariate and multivariate logistic regression models were used to analyse risk factors for inadequately dosing.ResultsA total of 262 FQ prescriptions for unique pa-tients were identified. Most children (57.6%) had signifi-cant chronic comorbidity such as any type of cancer, a neurologic disease, or congenital anomalies of the kid-neys and urinary tract. Ciprofloxacin was by far the most frequently prescribed FQ, representing 253 prescriptions (96.6%). Overall, the number of on-label FQ prescriptions was 43 (16.4%), and prescription was guided by a micro-bial culture in 62 cases (35.1%). 79 prescriptions (30.2%), of which 78 ciprofloxacin prescriptions, were considered to be inaccurately dosed. Underdosing was the most common type, as 57.1% of all inaccurately dosed pre-scriptions were underdosed. In the univariate logistic regression analysis, children younger than 6 years of age were at particular risk of receiving an inadequately dosed prescription. In the final multivariate logistic regression model, when controlled for the sort of FQ prescribed, Odds Ratios for infants and preschool children remained statistically significant.ConclusionFQ were often prescribed off-label and not guided by bacteriological findings in our study popula-tion. Dosing errors were common, particularly in infants and preschool children. FQ prescriptions for children should be improved by specific paediatric antimicrobial stewardship teams.

BackgroundNowadays, academic researchers, pharma-ceutical companies and regulatory authorities are more aware of the need for paediatric drug research. Conse-quently, more academic and industry-driven paediatric trials are conducted to evaluate the efficacy and safety of new drugs and to a lesser extent of off-patent and off-la-bel drugs. However little information is available on the burden associated with participating in clinical trials for the patients and their family/caregivers. In attempt of be-coming a Centre of Excellence in paediatric drug research it is important for us to fully understand this burden.MethodsThis is a retrospective, single centre, observa-tional study. A questionnaire will be designed focusing on the overall costs and time investment for the participants and their caregivers. Topics of interest will be absenteeism at school, at work or in leisure; number of specific study related visits (out of standard of care); financial reward by the sponsor; etc. Additional questions will gauge the per-ception and experience of the patients and their parents. We will contact the parents of patients who participated in either an academic or industry driven trial between 2010 and 2017 at the departments of paediatric nephrol-ogy and gastroenterology of the Elisabeth Children’s Hospital (Ghent University Hospital). We will display the results of this questionnaire by using descriptive statistics.DiscussionBy evaluating the results, we will identify what brings most burden to patients and their family/caregivers in participating in clinical trials. This will enable us to better understand this burden and eventually to anticipate by more and better information and support during the participation. This may increase compliance, especially important in drug trials. The data can help us to include these aspects in discussions with both ethical committee and sponsors (industry) during the develop-ment of the study design and during negotiation of the clinical trial agreement (inclusive of some compensation) between research centres and sponsors.

BackgroundThe Paediatric Regulation1 was launched ten years ago. As was also identified in the ten year report2, this regulation has had a positive impact on paediatric research in Europe. However, some specific patient pop-ulations (such as neonates, critically ill children, children with comorbidities) do not receive enough attention in paediatric drug development. Furthermore, the top-down approach (from adults to children) results in considerable delays in making medicines available to children. For most of the drugs long term follow-up is missing.MethodsThe SAFE-PEDRUG project was initiated in Belgium in 2014 and is a collaboration of experts in pae-diatrics, pharmaceutical sciences, veterinary medicine, and ethics of three Belgian universities: Ghent Universi-ty, KULeuven, and Vrije Universiteit Brussel. An advisory board and stakeholder group consisting of national and international stakeholders support this consortium in the valorisation of results.ResultsThe SAFE-PEDRUG project explored the value of the porcine juvenile animal model3 and PK modelling4 (population pharmacokinetics and physiological-ly based pharmacokinetic modelling) in providing prior paediatric PK/PD knowledge, before the actual adult trials have been completed. For the evaluation of this approach, three case compounds were selected: des-mopressin, lisinopril, and fluoroquinolones. The results of the models are plotted against human paediatric data, including data in neonates and critically ill children.DiscussionA close collaboration of experts and stake-holders can help to tailor paediatric clinical trials to the needs of children. Pharmaceutical industry and regulato-ry authorities are key players in the paediatric drug de-velopment process. However, academia can also play an important role in rendering the paediatric drug development process more efficient by development and correct use of innovative tools. Besides, academia should defend the rights of the most important stakeholders: patients and their parents. During the SAFE-PEDRUG project additional opportunities for academia have been identified: initiation of networking; centralisation in registries and networks to improve transparency and efficiency; and education of paediatric clinical pharmacologists.

BackgroundThe intra-patient variability in tacrolimus exposure (TAC-IPV) after paediatric liver transplantation and its impact on patient outcomes has been poorly studied. The present study aims to investigate whether there is a trend in TAC-IPV during the first 5 years post transplantation, which variables influence IPV and wheth-er the IPV during the first year is associated with liver transplantation outcomes in paediatric patients.MethodsWe conducted a single centre retrospective study including 41 living paediatric patients transplanted between January 2003 and September 2016 at the Ghent University Hospital. The intra-patient variability in the dose-adjusted tacrolimus pre-dose concentrations was calculated yearly during the first five years following trans-plantation, expressed as coefficient of variation (CV%1–5) The difference in CV% in the years following transplanta-tion was analysed using the Friedman test. A linear uni-variate and multivariate regression analysis was applied to identify factors associated with TAC-IPV. The following parameters were tested: age, gender, origin, the number of missed clinic appointments as a surrogate marker for ther-apy adherence, the total number of medications, concom-itant medications potentially interfering with TAC metabo-lism-CYP3A4/A5 inductors or inhibitors and biochemical parameters. Logistic and linear regression models were fit-ted to test an association of TAC-IPV with patient outcomes: need for biopsy during year 1, 3 and 5; hypertension and renal function at 1, 3 and 5 years; acute rejection and CMV/EBV viremia during year 1 post-transplantation.ResultsWe identified a significant decrease in TAC-IPV during the first 3 years after transplantation with the me-dian CV%1=39,4%; CV%2=30,9%; CV%3=28,5% (p=0,004), after which the CV% reaches a plateau (CV%4=23,6% en CV%5=28,9%). Multivariate analysis showed that serum albumin in the first year (p=0,029), haematocrit in the third year (p=0,019) and the number of missed clin-ic appointments in the fifth year after transplantation (p=0,009) were associated with TAC-IPV.in the 1 st, 3rd and 5th year, respectively. Univariate analysis showed that CV%1 was significantly associated with the need for bi-opsy during the first year post-transplantation (p=0.036) and the occurrence of one or more episodes of acute al-lograft rejection during the first year post-transplantation (p=0.031). In univariate analysis a trend was observed for association with hypertension one year after transplan-tation (p=0,085). Multivariate logistic regression analysis confirmed that CV%1 was an independent factor associ-ated with the need for liver biopsy in the first year follow-ing liver transplantation. (p=0.05; Exp(B)=1.045).ConclusionAs expected, tacrolimus intra-patient vari-ability is higher during the first two years after transplantation. Our results suggest that while albumin and hae-matocrit are associated with TAC-IPV in the first 3 years, therapy adherence expressed as the number of missed clinic appointments is associated with TAC...