Pharmacokinetics of Ceftazidime in Children and Adolescents with Obesity.

PURPOSE: The aim of this study was to evaluate ceftazidime pharmacokinetics (PK) in a cohort that includes a predominate number of children and adolescents with obesity and assess the efficacy of competing dosing strategies. METHODS: A population PK model was developed using opportunistically collected plasma samples. For each dosing strategy, model-based probability of target attainment (PTA) estimates were computed for study participants using empirical Bayes estimates. In addition, the effects of body size and renal function on PTA were evaluated using stochastic model simulations with virtually generated subjects. RESULTS: Twenty-nine participants, 24 of whom were obese, contributed data towards the analysis. The median (range) age, body weight, and body mass index of participants were 12.2 years (2.3-20.6), 59.2 kg (8.4-121), and 25.2 kg/m2 (13.8-42.9), respectively. Administration of 50 mg/kg intravenously (IV) every 8 hours (q8h; max 6 g/day) or 40 mg/kg IV q6h (max 6 g/day) resulted in PTA values of ≥ 90% (minimum inhibitory concentration 8 mg/L) for the subset of obese participants with estimated glomerular filtration rates (GFR) ≥ ~ 80 mL/min/1.73 m2. However, for both regimens, stochastic model simulations denoted lower PTA values (< 90%) with increasing body weight for virtual subjects with GFR ≥ 120 mL/min/1.73 m2. Alternatively, permitting for a maximum daily dose of 8 g/day using a 40 mg/kg IV q6h regimen provided PTA values that were near or above target (90%) for virtual subjects between 10 to 120 kg with GFR ≥ 80 mL/min/1.73 m2. CONCLUSION: Our analysis suggests administration of 40 mg/kg IV q6h (max 8 g/day) maximizes PTA in children and adolescents with obesity and GFR ≥ 80 mL/min/1.73 m2. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01431326.

Population Pharmacokinetics of Milrinone in Infants, Children, and Adolescents.

Milrinone is a type 3 phosphodiesterase inhibitor used to improve cardiac output in critically ill infants and children. Milrinone is primarily excreted unchanged in the urine, raising concerns for toxic accumulation in the setting of renal dysfunction of critical illness. We developed a population pharmacokinetic model of milrinone using nonlinear mixed-effects modeling in NONMEM to perform dose-exposure simulations in children with variable renal function. We included children aged <21 years who received intravenous milrinone per clinical care. Plasma milrinone concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay (range 1-5000 ng/mL). We performed dose-exposure simulations targeting steady-state therapeutic concentrations of 100-300 ng/mL previously established in adults and children with cardiac dysfunction. We simulated concentrations over 48 hours in typical subjects with decreasing creatinine clearance (CrCl), estimated using the updated bedside Schwartz equation. Seventy-four patients contributed 111 plasma samples (concentration range, 4-634 ng/mL). The median (range) postmenstrual age (PMA) was 3.7 years (0-18), and median weight (WT) was 13.1 kg (2.6-157.7). The median serum creatinine and CrCl were 0.5 mg/dL (0.1-3.1) and 117.2 mL/min/1.73 m2 (13.1-261.3), respectively. A 1-compartment model characterized the pharmacokinetic data well. The final model parameterization was: Clearance (L/h) = 15.9*(WT [kg] / 70)0.75 * (PMA1.12 / (67.71.12 +PMA1.12 )*(CrCl / 117)0.522 ; and Volume of Distribution (L) = 32.2*(WT [kg] / 70). A loading dose of 50 µg/kg followed by a continuous infusion of 0.5 µg/kg/min resulted in therapeutic concentrations, except when CrCl was severely impaired at ≤30 mL/min/1.73 m2 . In this setting, a 25 µg/kg loading dose and 0.25 µg/kg/min continuous infusion resulted in therapeutic exposures.

Dosing and Safety of Off-label Use of Caffeine Citrate in Premature Infants.

OBJECTIVE: To characterize the dosing and safety of off-label caffeine citrate in a contemporary cohort of extremely premature infants. STUDY DESIGN: We used electronic health records (2010-2013) from 4 neonatal intensive care units to identify infants of ≤28 weeks of gestational age exposed to caffeine citrate. Safety outcomes included death, bronchopulmonary dysplasia, necrotizing enterocolitis, spontaneous intestinal perforation, intraventricular hemorrhage, patent ductus arteriosus ligation, seizures, and arrhythmias. We used multivariable logistic regression to evaluate the association of caffeine citrate exposure with clinical events. RESULTS: Of 410 infants with a median (IQR) gestational age of 26 (24-27) weeks, 95% received caffeine citrate for >0 days. Infants received a median (IQR) daily dose of 8 (5-10) mg/kg/day. Incidences of clinical events on day of caffeine citrate exposure were death 2%, patent ductus arteriosus ligation 12%, and medical and surgical necrotizing enterocolitis 5% and 4%, respectively. Bronchopulmonary dysplasia occurred in 37% of infants and was not associated with caffeine dose. Increased caffeine citrate dose was associated with lower odds of patent ductus arteriosus ligation and necrotizing enterocolitis. CONCLUSIONS: Caffeine citrate was used in extremely premature infants at younger gestation, at higher doses, and for longer durations than recommended on the drug label. Increased caffeine citrate exposure, dose, or therapy duration was not associated with increased risk of necrotizing enterocolitis.

Approaches for dealing with various sources of overdispersion in modeling count data: Scale adjustment versus modeling.

Overdispersion is a common problem in count data. It can occur due to extra population-heterogeneity, omission of key predictors, and outliers. Unless properly handled, this can lead to invalid inference. Our goal is to assess the differential performance of methods for dealing with overdispersion from several sources. We considered six different approaches: unadjusted Poisson regression (Poisson), deviance-scale-adjusted Poisson regression (DS-Poisson), Pearson-scale-adjusted Poisson regression (PS-Poisson), negative-binomial regression (NB), and two generalized linear mixed models (GLMM) with random intercept, log-link and Poisson (Poisson-GLMM) and negative-binomial (NB-GLMM) distributions. To rank order the preference of the models, we used Akaike's information criteria/Bayesian information criteria values, standard error, and 95% confidence-interval coverage of the parameter values. To compare these methods, we used simulated count data with overdispersion of different magnitude from three different sources. Mean of the count response was associated with three predictors. Data from two real-case studies are also analyzed. The simulation results showed that NB and NB-GLMM were preferred for dealing with overdispersion resulting from any of the sources we considered. Poisson and DS-Poisson often produced smaller standard-error estimates than expected, while PS-Poisson conversely produced larger standard-error estimates. Thus, it is good practice to compare several model options to determine the best method of modeling count data.

Incidental paranasal sinusitis on routine brain magnetic resonance scans: association with atherosclerosis.

BACKGROUND: Incidental paranasal sinusitis (IPS) is common on imaging for non-sinusitis disorders, usually without symptoms or obstructive features, and possibly arising from periodontitis (PD). PD associations with atherosclerosis have been widely reported. We test if IPS may also be associated with atherosclerosis. METHODS: IPS was scored retrospectively in a random sample of 180 magnetic resonance (MR) brain scans and compared with chart review for atherosclerosis (all subtypes), rhinosinusitis, and related factors (smoking, asthma, and relevant surgery). IPS was scored out of 30, from all sinuses, with maxillary sinuses weighted double volumetrically. Significant IPS (Sig IPS) was designated as 6 or more out of 30. Bivariate logistic regression was used to test for associations of Sig IPS to the clinical data, with multivariate analysis then testing for potential confounders. RESULTS: A total of 173 subjects were analyzed (7 exclusions). MR indications included suspected acute/prior stroke (22.0%). Sig IPS found in 20 (11.6%). Positive histories for atherosclerosis were cerebral, 57 (32.9%); coronary, 48 (27.7%); and peripheral arterial disease, 14 (8.1%). IPS ≥6 was strongly associated with cerebrovascular disease (odds ratio [OR] 6.0, p < 0.001), and less robustly to smoking (OR 2.9, p = 0.07) and rhinosinusitis (OR 2.4, p = 0.09). No associations with coronary or peripheral artery diseases were found. After controlling for smoking and rhinosinusitis, yielding significant subclinical sinusitis, the link of Sig IPS to cerebrovascular disease persisted (modified OR 5.2, p = 0.002). CONCLUSION: Significant incidental sinusitis, which is mostly subclinical sinusitis, is associated with cerebrovascular disease but not other atheroscleroses. This suggests possible common causation of both by PD.