RATIONALE Various in vitro, animal and limited human adult studies suggest a profound inhibitory effect of inflammation and disease on Cytochrome P450 3A (CYP3A)-mediated drug metabolism. Studies... Show moreRATIONALE Various in vitro, animal and limited human adult studies suggest a profound inhibitory effect of inflammation and disease on Cytochrome P450 3A (CYP3A)-mediated drug metabolism. Studies showing this relationship in critically ill patients are lacking, while clearance of many CYP3A drug substrates may be decreased, potentially leading to toxicity. OBJECTIVES To prospectively study the relationship between inflammation, organ failure and midazolam clearance, as validated marker of CYP3A mediated drug metabolism, in critically ill children. METHODS From 83 critically ill children (median age 5.1 months (range 0.02-202 months)), midazolam plasma levels (n=532), cytokines (e.g. IL-6, TNF-a), C-reactive protein (CRP) and organ dysfunction scores (PRISM II, PIM2, PELOD), as well as number of failing organs were prospectively collected. A population pharmacokinetic model to study the impact of inflammation and organ failure on midazolam pharmacokinetics was developed using NONMEM 7.3. MAIN RESULTS In a two-compartmental pharmacokinetic model, body weight was the most significant covariate for clearance and volume of distribution. Both CRP and organ failure were significantly associated with clearance (p<0.01), explaining both inter-individual and inter-occasional variability. In simulations a CRP of 300 mg/L was associated with a 65% lower clearance compared to 10 mg/L and three failing organs were associated with a 35% lower clearance compared to 1 failing organ. CONCLUSIONS Inflammation and organ failure strongly reduce midazolam clearance, a surrogate marker of CYP3A-mediated drug metabolism, in critically ill children. Hence, critically ill patients receiving CYP3A substrate drugs may be at risk of increased drug levels and associated toxicity. Show less
