The PBPK approach used in this study suggests a mechanistic reason for differences in bioavailability between adults and children. If verified, this would be the first example of differential first-pass metabolism in children and adults.
Objective
Limited data exist on the effects of therapeutic hypothermia (TH) on renal function and pharmacokinetics in pediatric patients after cardiac arrest (CA). The objective was to describe the differences in vancomycin disposition in pediatric patients following CA treated with either TH or normothermia (NT) using population pharmacokinetic modeling.
Design
Single-center, retrospective cohort study
Setting
A tertiary care hospital pediatric and cardiac intensive care unit
Patients
Fifty-two pediatric patients (30 days to 17 years old) who experienced a CA, received vancomycin, and were treated with TH (32–34°C) or NT (36.3–37.6°C) between January 1st, 2010 and September 30th, 2014 were reviewed.
Interventions
None.
Measurements/Results
A two-compartment model with linear elimination, weight effects on clearance (CL), inter-compartmental clearance (Q), central volume of distribution (V1), and peripheral volume of distribution (V2) adequately described the data despite high variability due to the small sample size. The typical value of clearance in this study was 4.48 L/h (0.19 L/h/kg0.75) for a normothermic patient weighing 70kg and a glomerular filtration rate (GFR) of 90 mL/min/1.73m2. Patients treated with normothermia, but with reduced or poor renal function (≤90 mL/min/1.73m2) had up to an 80% reduction in vancomycin clearance compared to those with normal renal function (90–140 mL/min/1.73m2). Patients with normal renal function, but treated with TH versus NT experienced up to 25% reduction in vancomycin clearance. Patients treated with TH and with poor renal function experienced up to an 84% reduction in vancomycin clearance.
Conclusion
Patients receiving hypothermia and/or with decreased renal function had lower vancomycin clearances based on a retrospectively fitted two compartment model in children who experience cardiac arrest.
Drug-induced nephrotoxicity is responsible for 20% to 60% of cases of acute kidney injury in hospitalized patients and is associated with increased morbidity and mortality in both children and adults. Antimicrobials are one of the most common classes of medications prescribed globally and also among the most common causes of nephrotoxicity. A broad range of antimicrobial agents have been associated with nephrotoxicity, but the features of kidney injury vary based on the agent, its mechanism of injury and the site of toxicity within the kidney. Distinguishing nephrotoxicity caused by an antimicrobial agent from other potential inciting factors is important to facilitate both early recognition of drug toxicity and prompt cessation of an offending drug, as well as to avoid unnecessary discontinuation of an innocuous therapy. This review will detail the different types of antimicrobial-induced nephrotoxicity: acute tubular necrosis, acute interstitial nephritis and obstructive nephropathy. It will also describe the mechanism of injury caused by specific antimicrobial agents and classes (vancomycin, aminoglycosides, polymyxins, antivirals, amphotericin B), highlight the toxicodynamics of these drugs and provide guidance on administration or monitoring practices that can mitigate toxicity, when known. Particular attention will be paid to paediatric patients, when applicable, in whom nephrotoxin exposure is an often-underappreciated cause of kidney injury.
BackgroundAge-dependent differences in pharmacokinetics exist for metabolically cleared medications. Differential contributions in the cytochrome P450 3A (CYP3A), CYP2C, and flavin-containing monooxygenases (FMOs) families have an important role in the metabolic clearance of a large number of drugs administered to children.MethodsUnlike previous semiquantitative characterization of age-dependent changes in the expression of genes and proteins (western blot analysis), this study quantifies both gene and absolute protein expression in the same fetal, pediatric, and adult hepatic tissue. Expression was then correlated with the corresponding functional activities in the same samples.ResultsCYP3A and FMO families showed a distinct switch from fetal (CYP3A7 and FMO1) to adult isoforms (CYP3A4 and FMO3) at birth, whereas CYP2C9 showed a linear maturation from birth into adulthood. In contrast, analysis of CYP2C19 revealed higher expression and catalytic efficiency in pediatric samples compared with that in fetal and adult samples. Further, CYP3A and FMO enzymes exhibited an unexpectedly higher functional activity in fetal samples not entirely explained by protein expression.ConclusionThese surprising findings suggest that CYP and FMO enzymes may encounter development-related differences in their microenvironments that can influence the enzyme activity in addition to protein expression levels.
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