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Study Objectives To determine whether a relationship exists between initial serum vancomycin trough concentrations and initial empirical vancomycin dose, patient weight, and patient age, and to determine the risks for vancomycin-associated nephrotoxicity in pediatric patients stratified by hospital setting. Design Stepwise linear and multinomial logistic regression analysis of retrospectively collected data. Setting Two geographically distinct children's tertiary care medical centers. Patients A total of 316 pediatric patients without preexisting renal dysfunction who were managed outside of the neonatal intensive care unit and were treated with at least 3 doses of vancomycin for gram-positive bacterial infections and had at least one serum vancomycin trough concentration between January 1, 2008, and July 31, 2010. Measurements and Main Results Elevated vancomycin trough concentrations had no statistically significant relationship with initial empirical vancomycin dosing across all hospital settings. Serum vancomycin trough concentrations (lower than 15 mg/L or 15–20 mg/L) were not associated with increased risk of nephrotoxicity. Concomitant nephrotoxic agents, however, including loop diuretics, vasopressors, angiotensin-converting enzyme (ACE) inhibitors, and nonsteroidal antiinflammatory drugs (NSAIDs) were significantly associated with the development of nephrotoxicity in medical-surgical and intensive care patients. Based on this analysis, use of loop diuretics and vasopressors increased the odds of developing nephrotoxicity (odds ratio [OR] 42.8 [p=0.001] and 18.4 [p=0.02], respectively). Use of NSAIDS and ACE inhibitors also increased the odds of developing nephrotoxicity (OR 18.6 [p=0.02] and 4.7 [p=0.03], respectively). Conclusion No significant associations were found between initial empirical weight-based vancomycin dosing or elevated serum trough concentrations and development of nephrotoxicity in children; rather, nephrotoxicity was associated with combination therapy with vancomycin and other potentially nephrotoxic agents.

Positive allosteric modulators (‘potentiators’) of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) have been shown to display a mechanism-based exposure–response continuum in preclinical species with procognitive electrophysiological and behavioral effects (‘efficacy’) at low exposures and motor coordination disruptions at progressively higher exposures. Due to the dose-capping nature of such motor coordination deficits, an exposure threshold-mediated adverse event (CAE), the adequacy of separation between the maximal total plasma compound concentration (Cmax) at a predicted clinically efficacious oral dose and this adverse event (AE) was explored in early drug research with three AMPAR potentiators considered potential candidates for clinical trials. In vitro metabolism studies in human liver microsomes and human hepatocytes demonstrated the metabolic clearance for each compound was predominately due to cytochromes P450 (CYP). Thus, for each compound's anticipated clinically efficacious dose, human Cmax variability following oral administration was assessed using Simcyp software, which combines its virtual human populations database using extensive demographic, physiological and genomic information with routinely collected compound-specific in vitro biochemical data to simulate and predict drug disposition. Using a combination of experimentally determined recombinant human CYP intrinsic clearances for CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, human binding factors, expected fraction absorbed and estimated steady-state volume of distribution, Simcyp simulations demonstrated that two of the three potentiators had acceptable projected Cmax variability (i.e. the 95th percentile Cmax did not breach CAE). This evaluation aided in the selection of compounds for preclinical progression, and represents a novel application of pharmacologically based pharmacokinetic (PBPK) software approaches to predict interpatient variability. Copyright © 2011 John Wiley & Sons, Ltd.

Study Objective. To evaluate traditional nomogram (TN) versus individualized pharmacokinetic gentamicin dosing practices in neonatal intensive care units, focusing on achieving target therapeutic concentrations (peak > 8 μg/ml, trough < 2 μg/ml), number of dosing changes, number of concentrations obtained, and evidence of nephrotoxicity. Design. Retrospective chart review. Setting. Three neonatal intensive care units. Patients. Three hundred nine infants prescribed gentamicin. Intervention. None. Measurements and Main Results. Sixty-seven percent of patients receiving pharmacokinetic dosing had initial peak concentrations of 8 μ/ml or greater compared with 7% of patients receiving TN dosing (p