ObjectivesTo determine the extent of inter-individual variation in clearance of midazolam in children and establish which factors are responsible for this variation.MethodsA systematic literature review was performed to identify papers describing the clearance of midazolam 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.Results25 articles were identified. Only 13 studies gave the full range of clearance values for individual patients. The CV was greater in critically ill patients (18%–170%) than non-critically ill patients (13%–54%). Inter-individual variation was a major problem in all age groups of critically ill patients. The CV was 72%–106% in preterm neonates, 18%–73% in term neonates, 31%–130% in infants, 21%–170% in children and 47%–150% in adolescents. The mean clearance was higher in children (1.1–16.7 mL/min/kg) than in neonates (0.78–2.5 mL/min/kg).ConclusionsLarge inter-individual variation was seen in midazolam clearance values in critically ill neonates, infants, children and adolescents.

ObjectivesThe 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.MethodsA 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.ResultsTwenty-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 16–9 7 % 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).ConclusionsLarge inter-individual variation was seen in morphine clearance values in critically ill neonates and infants.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-015-1843-x) contains supplementary material, which is available to authorized users.

ObjectivesTo 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.MethodsA 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.ResultsA 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).ConclusionsThe 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.