| Summary: | Inter-individual variation in pharmacokinetic parameters of drugs can have profound effects on drug safety in children. Midazolam and morphine are among the most commonly used drugs in critically children. Theophylline has seen several cycles of enthusiasm and unpopularity over the years, although oral theophylline is now rarely used, IV aminophylline is still used regularly in severe asthma. These drugs are metabolised by hepatic enzymes (CYP3A4, CYP1A2 and glucuronidation) which have variable expression. Three systematic reviews were conducted in order to explore the inter-individual variation of clearance of these drugs in children. The first systematic review evaluated the inter-individual variability of midazolam clearance in children. Midazolam is predominantly metabolised by CYP3A4. Twenty two PK studies were identified. The mean clearance of midazolam varied between 0.78 to 3.5 ml/min/kg in neonates and 1.1 to 15 ml/min/kg in children. Age was a statistically significant predictor of clearance (p < 0.05). Critical illness was however not a statistically significant predictor of midazolam clearance after adjusting for other covariates (p=0.279). There was a statistically significant difference between the coefficient of variation of midazolam clearance in preterm neonates (91%) and children (40%) (p=0.002). However, there was no significant difference between the CV in critically ill and non-critically ill children. A second systematic review evaluated the variability of theophylline clearance. Theophylline is metabolised by CYP1A2. Twenty nine studies were identified. Mean clearance of theophylline varied between 0.2 and 2 ml/min/kg. Age was a significant predictor of theophylline clearance (p<0.05). There was, however, no significant difference between the CV of theophylline in any age group. The CV of theophylline clearance was not significantly different between critically ill (35%) and non-critically ill (39%) (p=0.403). A sub-analysis of children also did not show any significant difference between critically ill and non-critically ill (p=0.418). A third systematic review evaluated the variability of morphine clearance in children. Morphine is metabolised by UGT. Twenty studies were identified. The mean clearance of the studies identified varied between 2 and 16 ml/min/kg in neonates and 19 to 52 ml/min/kg in children. Critical illness was not a statistically significant predictor of morphine clearance. Analyses of the limited data showed no statistically significant differences in CV between any age groups. There was also no statistically significant difference between the CV in critically ill and non-critically ill children. In all the studies, a major limitation was the limited number of PK studies in children. Invasive studies should be avoided in children therefore, a final systematic review evaluated the invasiveness of PK studies over two decades. The number of blood samples collected per child was significantly lower in studies carried out between 2004-2014 than those between 1981-1990 (p=0.013). Furthermore, the total volume of blood collected in 24 hours for PK studies was significantly lower in new decade than old (p=0.025). However, there was no difference in the volume of blood collected per sample. There were 35 population PK studies, all of which were new studies. The median number of blood samples in population PK studies (median 6, [IQR: 4-9]) was significantly lower than non-population PK studies (median: 8, [IQR: 6-10]) (p=0.007). In conclusion, age is a risk factor for inter-individual variation of midazolam clearance in children. It is also an important predictor of midazolam, morphine and theophylline clearance in children. Therefore, age appropriate dosing is important. More PK studies are required to determine the effect of critical illness on the variability of clearance of these drugs. The utilisation of population PK methods should be encouraged to minimise invasiveness of PK studies. New methodologies for reducing sample volumes and frequency should be considered in all studies.
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