Hippocampal Volume Reduction in Congenital Central Hypoventilation Syndrome

Children with congenital central hypoventilation syndrome (CCHS), a genetic disorder characterized by diminished drive to breathe during sleep and impaired CO2 sensitivity, show brain structural and functional changes on magnetic resonance imaging (MRI) scans, with impaired responses in specific hippocampal regions, suggesting localized injury

A Translational Pharmacokinetic Rat Model of Cerebral Spinal Fluid and Plasma Concentrations of Cefepime

This study defines the transit of cefepime between plasma and cerebral spinal fluid (CSF) in a rat model. Male Sprague-Dawley rats received cefepime intravenously. Plasma samples were obtained via a second dedicated intravenous catheter. CSF sampling occurred via an intracisternal catheter. Drug exposures and transfer from the plasma to the CSF during the first 24 h were calculated. The median CSF/blood percentage of penetration was 19%. Cefepime transit to the CSF is rapid and predictable in the rat model. This model will be highly useful for understanding the therapeutic window for cefepime and neurotoxicity.This study sought to define the transit of cefepime between plasma and cerebral spinal fluid (CSF) in a rat model. Male Sprague-Dawley rats received cefepime intravenously. A total daily dose of 150 mg/kg of body weight/day was administered as a single injection every 24 h for 4 days. Plasma samples were obtained via a second dedicated intravenous catheter. CSF sampling occurred via an intracisternal catheter. Cefepime levels in plasma and CSF were quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic (PK) analyses were conducted using Pmetrics for R. PK parameters and exposures during the first 24 h (i.e., area under the concentration-time curve from 0 to 24 h [AUC0–24] and maximum concentration of drug in serum from 0 to 24 h [Cmax 0–24]) were calculated from Bayesian posteriors. CSF penetration was estimated by comparing the exposure profiles between plasma and the CSF. Eleven rats contributed PK data. A four-compartmental model with a lag compartment for CSF fit the data well for both plasma (Bayesian [R2 = 0.956]) and CSF (Bayesian [R2 = 0.565]). Median parameter values (with the coefficient of variation percentage [CV%] in parentheses) for the rate constants to CSF from the lag compartment (K34), to the central compartment from the CSF compartment (K41), and to the lag compartment from the central compartment (K13) were 2.96 h−1 (116.27%), 0.47 h−1 (54.86%), and 0.13 h−1 (23.42%), respectively. The elimination rate constant (kel) was 3.15 h−1 (7.5%). Exposure estimation revealed a plasma median (with interquartile range [IQR] in parentheses) half-life, AUC0–24, and Cmax 0–24, of 1.7 (1.5 to 1.9) h, 111.3 (95.7 to 136.5) mg · 24 h/liter, and 177.8 (169.7 to 236.4) μg/ml, from the first dose, respectively. Exposure estimation of CSF demonstrated a median (with IQR in parentheses) AUC0–24 and Cmax 0–24 of 26.3 (16.6 to 43.1) mg · 24 h/liter and 6.8 (5.2 to 9.4) μg/ml, respectively. The median CSF/blood percentage of penetration was 19%. Cefepime transit to the CSF is rapid and predictable in the rat model. This model will be highly useful for understanding the therapeutic window for cefepime and neurotoxicity

A Review of the Clinical Pharmacokinetics of Polymyxin B

Polymyxin B remains an antibiotic of last resort because of its toxicities. Although newer therapies are becoming available, it is anticipated that resistance to these agents will continue to emerge, and understanding the safest and most efficacious manner to deliver polymyxin B will remain highly important. Recent data have demonstrated that polymyxin B may be less nephrotoxic than colistin. Pharmacokinetically, polymyxin B is primarily eliminated via non-renal pathways, and most do not recommend adjusting the dose for renal impairment. However, some recent studies suggest a weak relationship between polymyxin B clearance and patient creatinine clearance. This review article will describe the clinical pharmacokinetics of polymyxin B and address relevant issues in chemistry and assays available

Development of Population and Bayesian Models for Applied Use in Patients Receiving Cefepime

Understanding pharmacokinetic disposition of cefepime, a β-lactam antibiotic, is crucial for developing regimens to achieve optimal exposure and improved clinical outcomes. This study sought to develop and evaluate a unified population pharmacokinetic model in both pediatric and adult patients receiving cefepime treatment.Multiple physiologically relevant models were fit to pediatric and adult subject data. To evaluate the final model performance, a withheld group of 12 pediatric patients and two separate adult populations were assessed.Seventy subjects with a total of 604 cefepime concentrations were included in this study. All adults (n = 34) on average weighed 82.7\ua0kg and displayed a mean creatinine clearance of 106.7\ua0mL/min. All pediatric subjects (n = 36) had mean weight and creatinine clearance of 16.0\ua0kg and 195.6\ua0mL/min, respectively. A covariate-adjusted two-compartment model described the observed concentrations well (population model R, 87.0%; Bayesian model R, 96.5%). In the evaluation subsets, the model performed similarly well (population R, 84.0%; Bayesian R, 90.2%).The identified model serves well for population dosing and as a Bayesian prior for precision dosing

Pharmacokinetic Disposition of Amiodarone When Given with an Intralipid Rescue Strategy

While the antiarrhythmic drug amiodarone is commonly used in clinical practice, it has a narrow therapeutic index that can lead to acute overdose. One proposed method to deal with this toxicity is lipid emulsion therapy, which may potentially quench the free amiodarone in blood and prevent its further distribution to target organs and tissues. In this study, we utilize an established swine model to examine the effects of Intralipid™ (IL) administration for acute amiodarone toxicity. A total of 14 pigs received an overdose of intravenous amiodarone. After twenty minutes, half of the pigs (n = 7) received IL while the control group (n = 7) received normal saline. Serum concentrations of amiodarone were then analyzed using a validated high-performance liquid chromatography (HPLC) method. Noncompartmental pharmacokinetic analyses were performed on the observed concentrations. There were no statistical differences in the area under the concentration time curve (6 h) or clearance, but there was a difference in the half-life between the two groups (3.12 vs. 0.85 h, p = 0.01). The administration of IL did not statistically change the overall exposure of amiodarone in the blood in the first 6 h; however, trends toward prolonged blood retention in the IL group were seen

Use of Simulation Strategies to Predict Subtherapeutic Meropenem Exposure Caused by Augmented Renal Clearance in Critically Ill Pediatric Patients With Sepsis

ObjectivesThe objectives of this study were to 1) define extent and potential clinical impact of increased or decreased renal elimination of meropenem in children with sepsis, based on analysis of renal function during the first 2 days of PICU stay; and 2) estimate the risk of subtherapeutic meropenem exposure attributable to increased renal clearance.MethodsThis retrospective study evaluated patients with a diagnosis of sepsis, receiving meropenem from the PICU at Rady Children's Hospital San Diego from 2015-2017. Meropenem exposure was estimated by using FDA-approved doses (20 and 40 mg/kg/dose) on day 1 and day 2 of PICU stay, based on a population pharmacokinetic (PK) model. For this population with sepsis, we assessed time-above-minimum inhibitory concentration (T>MIC) for pathogen MICs.ResultsMeropenem treatment was documented in 105 episodes of sepsis with a 48% rate of pathogen detection. By day 2, increased eGFR (>120 mL/min/1.73 m2) was documented in 49% of patients, with 17% meeting criteria for augmented renal clearance ([ARC] >160 mL/min/1.73 m2) and 10%, for decreased function. Simulations documented that 80% of PICU patients with ARC did not achieve therapeutic meropenem exposure for Pseudomonas aeruginosa with a MIC of 2, using standard doses to achieve a pharmacodynamic goal of 80% T>MIC.ConclusionsApproximately 3 of every 20 children with sepsis exhibited ARC during the first 48 hours of PICU stay. Simulations documented an increased risk for subtherapeutic meropenem exposure, suggesting that higher meropenem doses may be required to achieve adequate antibiotic exposure early in the PICU course