Inter-individual variation in morphine clearance in children.

OBJECTIVES: The aim of the study was to determine the extent of inter-individual variation in clearance of intravenous morphine in children and to establish which factors are responsible for this variation. METHODS: A systematic literature review was performed to identify papers describing the clearance of morphine in children. The following databases were searched: Medline, Embase, International Pharmaceutical Abstracts, CINAHL, and Cochrane library. From the papers, the range in plasma clearance and the coefficient of variation (CV) in plasma clearance were determined. RESULTS: Twenty-eight studies were identified. After quality assessment, 20 studies were included. Only 10 studies gave clearance values for individual patients. The majority of the studies were in critically ill patients. Inter-individual variability of morphine clearance was observed in all age groups, but greatest in critically ill neonates (both preterm and term) and infants. In critically ill patients, the CV was 16-97% in preterm neonates, 24-87% in term neonates, 35 and 134% in infants, 39 and 55% in children, and 74% in adolescents. The CV was 37 and 44% respectively in non-critically ill neonates and infants. The mean clearance was higher in children (32 and 52 ml min(-1) kg(-1)) than in neonates (2 to 16 ml min(-1) kg(-1)). CONCLUSIONS: Large inter-individual variation was seen in morphine clearance values in critically ill neonates and infants.

Safety of fluconazole in paediatrics: a systematic review.

PURPOSE: To determine the safety of fluconazole in neonates and other paediatric age groups by identifying adverse events (AEs) and drug interactions associated with treatment. METHODS: A search of EMBASE (1950-January 2012), MEDLINE (1946-January 2012), the Cochrane database for systematic reviews and the Cumulative Index to Nursing and Allied Health Literature (1982-2012) for any clinical study about fluconazole use that involved at least one paediatric patient (≤17 years) was performed. Only articles with sufficient quality of safety reporting after patients' exposure to fluconazole were included. RESULTS: We identified 90 articles, reporting on 4,209 patients, which met our inclusion criteria. In total, 794 AEs from 35 studies were recorded, with hepatotoxicity accounting for 378 (47.6 %) of all AEs. When fluconazole was compared with placebo and other antifungals, the relative risk (RR) of hepatotoxicity was not statistically different [RR 1.36, 95 % confidence interval (CI) 0.87-2.14, P = 0.175 and RR 1.43, 95 % CI 0.67-3.03, P = 0.352, respectively]. Complete resolution of hepatoxicity was achieved by 84 % of patients with follow-up available. There was no statistical difference in the risk of gastrointestinal events of fluconazole compared with placebo and other antifungals (RR 0.81, 95 % CI 0.12-5.60, P = 0.831 and RR 1.23, 95 %CI 0.87-1.71, P = 0.235, respectively). There were 41 drug withdrawals, 17 (42 %) of which were due to elevated liver enzymes. Five reports of drug interactions occurred in children. CONCLUSION: Fluconazole is relatively safe for paediatric patients. Hepatotoxicity and gastrointestinal toxicity are the most common adverse events. It is important to be aware that drug interactions with fluconazole can result in significant toxicity.

A prospective study to assess the palatability of analgesic medicines in children.

AIM: This study examined children's opinions on the taste of three analgesic medicines: paracetamol, ibuprofen and codeine. BACKGROUND: Many medicines for children are unpleasant and unacceptable. Research has shown that children's taste preferences differ to adults, in whom palatability is often tested. Little British research exists on children's opinions on the palatability of medicines. This study aimed to address this gap in knowledge. DESIGN: Prospective observational study. METHODS: Between May-September 2008, hospital inpatients aged 5-16 years rated the taste of required analgesics on a 100-mm visual analogue scale. This incorporated a 5-point facial hedonic scale. They were also asked their favourite flavour and colour for a medicine. RESULTS: A total of 159 children took part. Eighty-five males (53·5%) and 74 females (46·5%). The median age was 8 years (Inter-quartile range 6-11). The taste of ibuprofen was significantly preferred to paracetamol or codeine. Significant differences were observed depending if the medicine rated was taken first or second (for example pre-medication with paracetamol and ibuprofen). Younger children (5-8 years) were more likely to choose the extremes of the scale when grading than older children were. Preferred flavours on questioning were strawberry 44% and banana 17%. Favourite colours were pink 25·8% and red 20·8%, with girls more likely to choose pink and boys blue. CONCLUSION: Ibuprofen was the most palatable analgesic medicine tested. Children reported they preferred fruit flavours and colour was sex dependent. Nurses when administering two medicines together should consider giving the least palatable first, for example paracetamol before ibuprofen for pre-medication.

Systematic review of safety in paediatric drug trials published in 2007.

BACKGROUND: There is now greater involvement of children in drug trials to ensure that paediatric medicines are supported by sound scientific evidence. The safety of the participating children is of paramount importance. Previous research shows that these children can suffer moderate and severe adverse drug reactions (ADRs) in clinical trials, yet very few of the trials designated a data safety monitoring board (DSMB) to oversee the trial. METHODS: Safety data from a systematic review of paediatric drug randomised controlled trials (RCTs) published in 2007 were analysed. All reported adverse events (AEs) were classified and assessed to determine whether an ADR had been experienced. ADRs were then categorised according to severity. Each trial report was examined as to whether an independent DSMB was in place. RESULTS: Of the 582 paediatric drug RCTs analysed, 210 (36%) reported that a serious AE had occurred, and in 15% mortality was reported. ADRs were detected in more than half of the RCTs (305); 66 (11%) were severe, and 79 (14%) were moderate. Severe ADRs involved a wide range of organ systems and were frequently associated with cytotoxic drugs, antiparasitics, anticonvulsants and psychotropic drugs. Two RCTs reported significantly higher mortality rates in the treatment group. Only 69 (12%) of the RCTs stated there was a DSMB. DSMBs terminated five RCTs and changed the protocol in one. CONCLUSIONS: Children participating in drug RCTs experience a significant amount and a wide range of ADRs. DSMBs are needed to ensure the safety of paediatric participants in clinical drug trials.

Pharmacokinetics of buccal and intranasal lorazepam in healthy adult volunteers.

PURPOSE: To investigate the plasma-concentration profile of lorazepam when administered by the intranasal and buccal routes to determine their utility for the treatment of prolonged seizures. METHODS: On two occasions separated by at least 7 days washout, 12 healthy adult male volunteers received 2 mg of lorazepam via the intranasal or buccal route. Blood samples were collected at time periods from 0 to 48 h, and pharmacokinetic parameters were determined. RESULTS: Lorazepam was well absorbed from both administration routes; however, there was a more pronounced lag phase with the buccal route and absorption was more rapid from the intranasal route. CONCLUSIONS: Intranasal lorazepam has more favourable pharmacokinetics than buccal lorazepam when considering the need for the rapid blood concentrations required for seizure termination. Further clinical evaluation of this route is required.

A systematic review of pharmacokinetics studies in children with protein-energy malnutrition.

OBJECTIVE: protein energy malnutrition (PEM) is a nutritional problem affecting many children world-wide. Its association with a wide spectrum of infections necessitates multiple drug therapies. A systematic review was performed to determine the effects of PEM on drug pharmacokinetics. METHODS: literature searches in the MEDLINE and EMBASE databases (January 1960 to December 2009) were performed. Malnutrition, undernutrition, underweight, protein-energy malnutrition, protein-calorie malnutrition, marasmus, marasmic-kwashiorkor or kwashiorkor was the medical subject heading (MeSH) descriptor used. Inclusion criteria were abstracts that assessed or discussed absorption, distribution, metabolism, elimination, clearance, pharmacokinetics or pharmacodynamics of drugs, except micronutrients and appetite-stimulating drugs. RESULTS: altogether, 41 publications were identified. A total of 34 drugs were studied. The absorption of 18 drugs was studied; the extent of absorption (AUC) was unaffected for 10 drugs. The plasma protein binding of 20 drugs was evaluated; it was significantly reduced for 12 drugs. The volume of distribution (Vd) of 13 drugs was evaluated; it was, however, unaffected for most of the drugs. The effect of PEM on total clearance and the half-life of drugs primarily metabolised by the liver was studied for 8 drugs. There was decreased total clearance and an associated increased half-life of 5 drugs. For 2 drugs (chloramphenicol and quinine), different degrees of PEM affected total clearance differently. The total clearance of six drugs primarily eliminated by the kidneys was studied; it was unaffected for four drugs, but significantly decreased for two drugs (cefoxitin and penicillin). CONCLUSIONS: considering the proportion of children affected with PEM world-wide, there have been relatively few pharmacokinetic studies of drugs frequently used for their treatment. More studies are therefore required to establish the appropriate dose and safety of these drugs for PEM children. The studies need to recognise that PEM is a disease spectrum and should further look at the differential effects of kwashiorkor and marasmus on drug pharmacokinetics in children.

Paediatric Rational Prescribing: A Systematic Review of Assessment Tools.

Rational prescribing criteria have been well established in adult medicine for both research and quality improvement in the appropriate use of medicines. Paediatric rational prescribing has not been as widely investigated. The aims of this review were to identify and provide an overview of all paediatric rational prescribing tools that have been developed for use in paediatric settings. A systematic literature search was made of MEDLINE, Embase, CINAHL and IPA from their earliest records until July 2019 for all published paediatric rational prescribing tools. The characteristics of the tools were recorded including method of development, types of criteria, aspects of rational prescribing assessed, and intended practice setting. The search identified three paediatric rational prescribing tools: the POPI (Pediatrics: Omissions of Prescriptions and Inappropriate Prescriptions) tool, the modified POPI (UK) tool, and indicators of potentially inappropriate prescribing in children (PIPc). PIPc comprises explicit criteria, whereas POPI and the modified POPI (UK) use a mixed approach. PIPc is designed for use in primary care in the UK and Ireland, POPI is designed for use in all paediatric practice settings and is based on French practice standards, and the modified POPI (UK) is based on UK practice standards and is designed for use in all paediatric practice settings. This review describes three paediatric rational prescribing tools and details their characteristics. This will provide readers with information for the use of the tools in quality improvement or research and support further work in the field of paediatric rational prescribing.

Modifying a Paediatric Rational Prescribing Tool (POPI) for Use in the UK.

Rational prescribing tools can be used by individual prescribers, organisations, and researchers to evaluate the quality of prescribing for research and quality improvement purposes. A literature search showed that there is only one tool for evaluating rational prescribing for paediatric patients in hospital and outpatient settings. The Pediatrics: Omission of Prescriptions and Inappropriate Prescriptions (POPI) tool was developed in France and comprises 105 criteria. The aim of this study was to modify this tool to facilitate its use in paediatric practice in the United Kingdom (UK). POPI criteria were compared to relevant UK clinical guidelines from the National Institute for Health and Care Excellence, the Scottish Intercollegiate Guideline Network and the British National Formulary for Children. Where guidelines differed, criteria were modified to reflect UK guidance. If there were no relevant guidelines or directly contradictory guidelines, criteria were removed. Overall, no change was made to 49 criteria. There were 29 modified to concord with UK guidelines. Four criteria were reduced to two criteria due to being linked in single guidelines. Twenty-three criteria were omitted, due to the absence of relevant UK guidance or directly conflicting UK practice, including one entire clinical category (mosquitos). One category title was amended to parallel UK terminology. The modified POPI (UK) tool comprises of eighty criteria and is the first rational prescribing tool for the evaluation of prescribing for children in hospital and outpatient settings in the UK.

Safety of antiepileptic drugs in children and young people: A prospective cohort study.

PURPOSE: This study aims to describe the incidence of adverse drug reactions (ADRs) in children receiving antiepileptic drugs (AEDs) and compare ADRs to the individual drugs when given as monotherapy. METHOD: Paediatric patients (≤18 years old) were enrolled for this prospective observational study over a 6-month period, between September 2015 and March 2016. Adverse reactions to antiepileptic drugs (AEDs) were elicited at the time of enrolment and after 3 months using the Paediatric Epilepsy Side Effects Questionnaire. RESULTS: A total of 1139 suspected ADRs were reported in 124 participants. Eighteen different AEDs were prescribed. Sixty-six children (53%) were receiving AED monotherapy at the time of recruitment; 34/66 (52%) of whom received new generation AEDs. Levetiracetam was the most frequently prescribed AED (62/124, 50%). When only children receiving AED monotherapy were considered, fatigue, drowsiness, weight gain, dizziness were less likely with levetiracetam (p < .01). Slow thinking and decreased concentration were less likely with levetiracetam or carbamazepine than valproic acid (p < .05). Five patients (four on polytherapy) discontinued AED treatment due to ADRs and 2 had a dose reduction. CONCLUSIONS: Levetiracetam and carbamazepine were better tolerated than sodium valproate.

Comparison of oral amoxicillin and intravenous benzyl penicillin for community acquired pneumonia in children (PIVOT trial): a multicentre pragmatic randomised controlled equivalence trial.

OBJECTIVE: To ascertain whether therapeutic equivalence exists for the treatment of paediatric community acquired pneumonia by the oral and intravenous (IV) routes. METHODS: A multicentre pragmatic randomised controlled non-blinded equivalence trial was undertaken in eight paediatric centres in England (district general and tertiary hospitals). Equivalence was defined as no more than a 20% difference between treatments of the proportion meeting the primary outcome measure at any time. 246 children who required admission to hospital and had fever, respiratory symptoms or signs and radiologically confirmed pneumonia were included in the study. Exclusion criteria were wheeze, oxygen saturations <85% in air, shock requiring >20 ml/kg fluid resuscitation, immunodeficiency, pleural effusion at presentation requiring drainage, chronic lung condition (excluding asthma), penicillin allergy and age <6 months. The patients were randomised to receive oral amoxicillin for 7 days (n = 126) or IV benzyl penicillin (n = 120). Children in the IV group were changed to oral amoxicillin after a median of six IV doses and received 7 days of antibiotics in total. The predefined primary outcome measure was time for the temperature to be <38 degrees C for 24 continuous hours and oxygen requirement to cease. Secondary outcomes were time in hospital, complications, duration of oxygen requirement and time to resolution of illness. RESULTS: Oral amoxicillin and IV benzyl penicillin were shown to be equivalent. Median time for temperature to settle was 1.3 days in both groups (p<0.001 for equivalence). Three children in the oral group were changed to IV antibiotics and seven children in the IV group were changed to different IV antibiotics. Median time to complete resolution of symptoms was 9 days in both groups. CONCLUSION: Oral amoxicillin is effective for most children admitted to hospital with pneumonia (all but those with the most severe disease who were excluded from this study). Prior to this study, the British Thoracic Society guidelines on childhood pneumonia could not draw on evidence to address this issue. This will spare children and their families the trauma and pain of cannulation, and children will spend less time in hospital.

What motivates British parents to consent for research? A questionnaire study.

BACKGROUND: Informed consent is the backbone of a clinical trial. In children this is given by their parents. There have been many studies in the neonatal population but little is known about the views of the parents of infants and young children from within the United Kingdom. The objectives of this study were to assess what motivates parents to consent to a randomised clinical trial (RCT), their feelings on consent and participation and the factors that would influence their decision to take part in a future study. METHODS: The setting was a multi-centre randomised but non-blinded equivalence trial of oral versus intravenous (IV) treatment for community acquired pneumonia in previously well children aged 6 months to 16 years in the UK (PIVOT Study). Parents were sent a postal questionnaire at the end of the study which included open and closed-ended questions. Fishers Exact Test was used to analyse associations in non parametric categorical data. RESULTS: 243 children were recruited into the PIVOT study. Of a possible 235, 136 questionnaires were returned (response rate 59%). Of those questionnaires returned; 98% of parents remembered consenting, 95% felt they were given enough time to make their decision and 96% felt they received enough information. Major reasons for participation were benefit to other children in the future 31%, contribution to science 27%, benefit to their own child 18%. Most parents (85%) did not feel obliged to participate. 62% felt there was an advantage to taking part and 18% felt there was a disadvantage. 91% of parents said they would take part in a similar study in the future, stating influences on their decision being benefit to their own child (91%) and benefit to all children (89%). CONCLUSION: The major motivation in parents consenting for their previously well child to participate in an RCT of therapy for an acute medical illness was to increase medical knowledge in the future. Most saw an advantage in taking part in the trial and did not feel obliged to participate.

Anti-epileptic drug utilisation in paediatrics: a systematic review.

OBJECTIVES: This study aims to determine global anti-epileptic drug (AED) utilisation prevalence and describe utilisation trends in different countries. METHODS: Databases Embase (1980-May 2017), Medline (1946-May 2017) and PubMed were searched for original research on AED utilisation. All paediatric national or regional database studies and surveys were included. RESULTS: Twenty-one studies were identified. Five were excluded from the analysis as the data were collected before 2005, leaving 16 studies. Monotherapy regimen varied between 58% and 94% in different countries. In several of the studies, sodium valproate was the most frequently prescribed AED. However, there is a trend towards increasing utilisation of new-generation AEDs, particularly levetiracetam, in some countries. CONCLUSION: Monotherapy was used in 58%-94%of patients. There is increasing utilisation of the new-generation AEDs, in particular lamotrigine, levetiracetam and topiramate. Old-generation AEDs are still used in the majority of patients. There is a need for up-to-date studies to determine the prevalence of AEDs in children.

Retrospective review of paediatric case reports of Stevens-Johnson syndrome and toxic epidermal necrolysis with lamotrigine from an international pharmacovigilance database.

OBJECTIVES: This study aims to characterise paediatric reports with lamotrigine (LTG) and Stevens-Johnson syndrome or toxic epidermal necrolysis (SJS/TEN), and to explore whether potential risk factors can be identified. DESIGN: This is a retrospective review of suspected adverse drug reaction (ADR) reports. Reported time from LTG start to SJS/TEN onset, indication for use and dose was explored. To identify potential risk groups, report features (eg, ages, patient sex, co-reported drugs) for LTG and SJS/TEN were contrasted with two reference groups in the same database, using shrinkage logOR. SETTING: Reports were retrieved from VigiBase, the WHO global database of individual case safety reports, in January 2015. PATIENTS: Data for patients aged ≤17 years old were extracted. RESULTS: There were 486 reports of SJS/TEN in LTG-treated paediatric patients. Ninety-seven per cent of the cases with complete information on time to onset of SJS/TEN occurred within 8 weeks of initiation of LTG therapy. The median time to onset was 15 days (IQR: 10-22 days). The proportion of SJS/TEN with LTG and valproic acid (VPA) co-reporting was significantly more than non-cutaneous ADRs (43% vs 19%, (logOR: 1.60 (99% CI: 1.33 to 1.84)). CONCLUSIONS: The results suggest that VPA co-medication with LTG therapy is a risk factor for SJS/TEN in the paediatric population. Although this relationship has been identified from individual case reports, this is the first supportive study from a large compilation of cases. SJS/TEN risk is highest in first 8 weeks of treatment with LTG in children and clinicians should be aware of this risk during this period.

Protocol for a prospective observational study of adverse drug reactions of anti-epileptic drugs in children in the UK.

BACKGROUND: Epilepsy is a common chronic disease of children that can be treated with anti-epileptic drugs (AEDs). AEDs, however, have significant side effects. Newer AEDs are thought to have fewer side effects. There have, however, been few comparative studies of AED toxicity. The aim is to compare the safety profile of the most frequently used AEDs by performing a multicentre prospective cohort study. This protocol describes the planned study. DESIGN: A multicentre prospective cohort study of children on AED treatment in hospitals across the UK. Ethical approval will be obtained. SAMPLE SIZE: Three thousand children on treatment for epilepsy will be recruited from paediatric clinics. It is expected that this sample size will have the potential to compare toxicity between the most frequently used AEDs. DURATION OF STUDY: 24 months. OUTCOME MEASURE: Adverse drug reactions (ADRs) to AEDs. These will be identified by the use of a validated questionnaire, the Paediatric Epilepsy Side Effect Questionnaire. They will be evaluated using the Naranjo algorithm. Preventability will be assessed using the Schumock and Thornton scale. DISCUSSION: Toxicity of individual AEDs when given as monotherapy and polytherapy will be determined. Additionally, discontinuation rates due to ADRs will be determined. The data will assist clinicians in choosing AEDs with the least toxicity.

[A complete clinical trial register is already a reality in the paediatric field]. / Le registre européen des essais cliniques pédiatriques est une réalité.

Clinical trials have a fundamental role in promoting an evidence based use of drugs in adults and in children. However, it is often difficult to identify the few paediatric studies carried out and to thus implement knowledge derived from them. Furthermore, studies that are stopped prematurely or that have insignificant or negative results often remain unpublished, leading to duplication of effort by researchers, waste of resources and concealment of potentially toxic risks. The European Community decided to support the development of a European register of clinical trials in children as part of the Fifth Framework Thematic Programme "Quality of Life" in 2002. The project DEC-net is coordinated by the Laboratory of Mother and Child Health of the Mario Negri Institute for Pharmaceutical Research in Milan and currently involves members of four countries; France, Italy, Spain and the United Kingdom. It is unique in that it is the first population oriented clinical trial register. Such a register represents a useful source for planning new studies, promoting communications and collaborations between researchers, facilitating patient access and recruitment into trials, preventing trial duplication and inappropriate funding and identifying the therapeutic needs of children that remain neglected. It will also allow for active monitoring of new or evolved knowledge of drug therapies.

Learning Lessons from Adverse Drug Reactions in Children.

Drug toxicity is, unfortunately, a significant problem in children both in the hospital and in the community. Drug toxicity in children is different to that seen in adults. At least one in 500 children will experience an adverse drug reaction each year. For children in hospital, the risk is far greater (one in ten). Additionally, different and sometimes unique adverse drug reactions are seen in the paediatric age groups. Some of the major cases of drug toxicity historically have occurred in neonates. It is important that we understand the mechanism of action of adverse drug reactions. Greater understanding alongside rational prescribing should hopefully reduce drug toxicity in children in the future.

INTER-INDIVIDUAL VARIATION IN THEOPHYLLINE CLEARANCE IN CHILDREN.

BACKGROUND: Inter-individual variation in pharmacokinetics in children is an area where there has been little research. We wished to determine the extent of inter-individual variation in the clearance of theophylline in paediatric patients of different ages. METHODS: A systematic literature review was performed using the following databases; Embase (1974 to January 2013), Medline (1946 to January 2013), CINAHL (1937 to January 2013), International Pharmaceutical Abstracts (1970 to January 2013) and the Cochrane Library. From the papers, the range in plasma clearance and the coefficient of variation (CV) in plasma clearance were determined. RESULTS: A total of 56 articles reporting on 1,315 patients met our inclusion criteria. Twenty six studies gave individual data. The majority of the studies were in critically ill patients. Inter-individual variation was a major problem in all age groups. The CV was 9-93% in preterm neonates, 20-97% in term neonates, 18-52% in infants, 2-72% in children and 4.5-43% in adolescents. The mean clearance was higher in children (0.85 to 2 ml/min/kg) than in neonates (0.24 to 0.6 ml/min/kg). CONCLUSIONS: Large inter-individual variation was seen, especially in critically ill patients. Inter-individual variation was higher in neonates than children and adolescents.

Safety of Levetiracetam in Paediatrics: A Systematic Review.

OBJECTIVE: To identify adverse events (AEs) associated with Levetiracetam (LEV) in children. METHODS: Databases EMBASE (1974-February 2015) and Medline (1946-February 2015) were searched for articles in which paediatric patients (≤18 years) received LEV treatment for epilepsy. All studies with reports on safety were included. Studies involving adults, mixed age population (i.e. children and adults) in which the paediatric subpopulation was not sufficiently described, were excluded. A meta-analysis of the RCTs was carried out and association between the commonly reported AEs or treatment discontinuation and the type of regimen (polytherapy or monotherapy) was determined using Chi2 analysis. RESULTS: Sixty seven articles involving 3,174 paediatric patients were identified. A total of 1,913 AEs were reported across studies. The most common AEs were behavioural problems and somnolence, which accounted for 10.9% and 8.4% of all AEs in prospective studies. 21 prospective studies involving 1120 children stated the number of children experiencing AEs. 47% of these children experienced AEs. Significantly more children experienced AEs with polytherapy (64%) than monotherapy (22%) (p<0.001). Levetiracetam was discontinued in 4.5% of all children on polytherapy and 0.9% on monotherapy (p<0.001), the majority were due to behavioural problems. CONCLUSION: Behavioural problems and somnolence were the most prevalent adverse events to LEV and the most common causes of treatment discontinuation. Children on polytherapy have a greater risk of adverse events than those receiving monotherapy.

Invasiveness of pharmacokinetic studies in children: a systematic review.

OBJECTIVES: To explore whether pharmacokinetic (PK) studies in paediatric patients are becoming less invasive. This will be evaluated by analysing the number of samples and volume of blood collected for each study within four different decades. METHODS: A systematic literature review was performed to identify PK papers describing number of samples and volume of blood collected in studies of children aged 0-18 years. The following databases were searched: MEDLINE (1946 to December 2015), EMBASE (1974 to December 2015), International Pharmaceutical Abstracts (1970 to December 2015), CINAHL and Cochrane Library. RESULTS: A total of 549 studies were identified between 1974 and 2015. There were 52 studies between 1976 and 1985, 105 between 1986 and 1995, 201 between 1996 and 2005 and 191 between 2006 and 2015. The number of blood samples collected per participant increased between the first two decades (p=0.013), but there was a decrease in the number of samples in the subsequent two decades (p=0.044 and p<0.001, respectively). Comparing the first and last decades, there has been no change in the number of blood samples collected. There were no significant differences in volume collected per sample or total volume per child in any of the age groups. There was however a significant difference in the frequency of blood sampling between population PK studies (median 5 (IQR 3-7)) and non-population PK studies (median 8 (IQR 6-10); p=<0.001). CONCLUSIONS: The number of blood samples collected for PK studies in children rose in 1985-1995 and subsequently declined. There was no overall change in the volume of blood collected over the 4 decades. The usage of population PK methods reduces the frequency of blood sampling in children.