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WHAT IS ALREADY KNOWN ABOUT THIS PROJECT? • Mycophenolate mofetil (MMF) is an immunosuppressant drug used for the treatment and prevention of graft vs. host disease in blood or marrow transplantation and acute graft rejection in solid organ transplantation. • Mycophenolic acid (MPA) pharmacokinetics have not been thoroughly studied in paediatric blood or marrow transplant recipients and guidance for optimal dosing of mycophenolic acid in children is lacking. • Mycophenolic acid exhibits considerable inter‐ and intra‐patient pharmacokinetic variability in adults and paediatric transplant recipients. • The AUC of mycophenolic acid over a 12 h dose interval at steady‐state is generally agreed to be the most reliable metric associated with the risk of acute rejection. • Population pharmacokinetic analysis can utilize concentration information from both intensive sampling and sparse sampling to provide pharmacokinetic parameter estimates, estimates of inter‐ individual and intra‐individual variability in these parameters and allows patient characteristics explaining inter‐individual variability to be quantified. WHAT THIS STUDY ADDS • This study is one of the first investigations in which a population pharmacokinetic modelling approach was applied to assess the pharmacokinetics of both intravenous and oral MMF in children and young people undergoing blood or marrow and solid organ transplantation. • Bodyweight and concomitant ciclosporin were found to influence MPA pharmacokinetics. • This study evaluated current dosing strategies and found that they may be suboptimal for children weighing less than 10 kg. AIMS To characterize the population pharmacokinetics of mycophenolic acid (MPA) and evaluate dose regimens using a simulation approach and accepted therapeutic drug monitoring targets in children and young people undergoing blood or marrow, kidney and liver transplantation. METHODS MPA concentration–time data were collected using an age specific sampling protocol over 12 h. Some patients provided randomly timed but accurately recorded blood samples. Total and unbound MPA were measured by HPLC. NONMEM was employed to analyze MPA pharmacokinetic data. Simulations (n= 1000) were conducted to assess the suitability of the MPA dose regimens to maintain total MPA AUC(0,12 h) within the range 30 and 60 mg l−1 h associated with optimal outcome. RESULTS A two‐compartment pharmacokinetic model with first‐order elimination best described MPA concentration–time data. Population mean estimates of MPA clearance, inter‐compartmental clearance, volumes of distribution in the central and peripheral compartments, absorption rate constant and bioavailability were 6.42 l h−1, 3.74 l h−1, 7.24 l, 16.8 l, 0.39 h−1 and 0.48, respectively. Inclusion of bodyweight and concomitant ciclosporin reduced the inter‐individual variability in CL from 54.3% to 31.6%. Children with a bodyweight of 10 kg receiving standard MPA dose regimens achieve an MPA AUC below the target range suggesting they may be at a greater risk of acute rejection. CONCL...

Familial hypercholesterolaemia (FH) is a common genetic disorder affecting more than 8000 children and adolescents throughout Australia. It results in marked elevation in plasma low-density lipoprotein cholesterol levels from birth that predisposes individuals to premature coronary heart disease in adult life. The majority of children and adolescents with FH are undiagnosed, as symptoms and signs only develop after decades of hypercholesterolaemia. Cascade screening of family members after detecting FH in an index case is an effective approach that allows the diagnosis of FH to be made in the young, before significant atherosclerosis develops. With the availability of effective therapies, mainly statins, paediatricians are ideally placed to improve the outcomes of this disorder by detecting and managing hypercholesterolaemia in childhood, thereby preventing premature coronary artery disease. We describe a new paediatric model of care for FH.

BACKGROUND: Studies examining the foetal origins hypothesis suggest that small birth size may be a marker of foetal adaptations that programme future propensity to adult disease. We explore the hypothesis that birth size may relate to fat distribution in childhood and that fat distribution may be a link between birth size and adult disease. OBJECTIVE: To investigate the relationship between birth size and abdominal fat, blood pressure, lipids, insulin and insulin:glucose ratio in prepubertal children. DESIGN: Cross-sectional study, based on a birth cohort of consecutive full-term births. SUBJECTS: Two hundred and fifty-five (137 females) healthy, 7-and 8-y-old children. MEASUREMENTS: Body composition and abdominal fat was measured by dual energy X-ray absorptiometry. Lipid, glucose and insulin profiles were measured after an overnight fast and an automated BP monitor was used for blood pressure measurements. RESULTS: There was a negative association between abdominal fat and birth weight s.d. score across a range of normal birth weights (b ¼ 70.18; 95% CI ¼ 70.31 to 70.04, P ¼ 0.009) and a positive association with weight s.d. score at 7=8 y (b ¼ 0.35; 95% CI ¼ 0.24 to 0.46, P < 0.001). Children who were born with the lowest weight s.d. score and had the greatest weight s.d. score at 7=8 y had significantly more (P < 0.001) abdominal fat, as a percentage of total fat (6.53 AE 1.3%) than those who had the highest birth weight s.d. score and the lowest weight s.d. score at 7=8 y (4.14 AE 0.5%). Similar results were seen if head circumference, but not ponderal index, was used as an indicator of birth size. Increased abdominal fat was associated with higher total cholesterol:HDL cholesterol, higher triglyceride concentration and increased diastolic blood pressure. CONCLUSIONS: Birth weight independently predicted abdominal fat. Children with the highest amount of abdominal fat were those who tended to be born lighter and gained weight centiles. Increased abdominal fat was associated with precursor risk factors for ischaemic heart disease.

This is one of few studies of fat-soluble vitamin deficiency in children with CF in Australia. Fat-soluble vitamin testing is essential to identify deficiency in pancreatic-insufficient children who may be non-compliant to supplementation or require a higher supplement dose, and pancreatic-sufficient children who may be progressing to insufficiency. Testing of vitamin K-dependent factors needs consideration. Further studies are needed to monitor rates of vitamin deficiency in the CF community.