Dose Escalation Pharmacokinetic Study of Intranasal Atomized Dexmedetomidine in Pediatric Patients With Congenital Heart Disease.

BACKGROUND: Atomized intranasal dexmedetomidine is an attractive option when sedation is required for pediatric patients as either premedication or the sole agent for noninvasive, nonpainful procedures. While intranasal dexmedetomidine is used frequently in this population, it is still unclear what dose and time of administration relative to the procedure will result in the optimal effect. Knowledge regarding the maximum concentration (C max ) and time to reach maximum concentration (T max ) of intranasally administered dexmedetomidine is the first step toward this. The risk of hemodynamic instability caused by increasing doses of dexmedetomidine necessitates a greater understanding of the pharmacokinetics in children. METHODS: Sixteen pediatric patients 2 to 6 years of age undergoing elective cardiac catheterization received 2 or 4 µg/kg dexmedetomidine intranasally. Plasma concentrations were determined by liquid chromatography-tandem mass spectrometry with a validated assay. Descriptive noncompartmental analysis provided estimates of peak concentrations and time to reach peak concentrations. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling. Simulations were performed using the final model to assess dose concentrations with an alternative dosing regimen of 3 µg/kg. RESULTS: A median peak plasma concentration of 413 pg/mL was achieved 91 minutes after 2 µg/kg dosing, and a median peak plasma concentration of 1000 pg/mL was achieved 54 minutes after 4 µg/kg dosing. A 1-compartment pharmacokinetic model adequately described the data. Three subjects in the 4 µg/kg dosing cohort achieved a dose-limiting toxicity (DLT), defined as a plasma dexmedetomidine concentration >1000 pg/mL. None of these subjects had any significant hemodynamic consequences. Simulations showed that no subjects would experience a level >1000 pg/mL when using a dose of 3 µg/kg. CONCLUSIONS: Concentrations associated with adequate sedation can be achieved with intranasal dexmedetomidine doses of 2 to 4 µg/kg in children 2 to 6 years of age. However, 50% of our evaluable subjects in this cohort reached a plasma concentration >1000 pg/mL. Doses of 3 µg/kg may be optimal in this population, with simulated concentrations remaining below this previously established toxicity threshold. Further studies correlating concentrations with efficacy and adverse effects are needed.

Development and validation of a volumetric absorptive microsampling- liquid chromatography mass spectrometry method for the analysis of cefepime in human whole blood: Application to pediatric pharmacokinetic study.

Cefepime is a fourth-generation cephalosporin antibiotic with an extended spectrum of activity against many Gram-positive and Gram-negative bacteria. There is a growing need to develop sensitive, small volume assays, along with less invasive sample collection to facilitate pediatric pharmacokinetic clinical trials and therapeutic drug monitoring. The volumetric absorptive microsampling (VAMS™) approach provides an accurate and precise collection of a fixed volume of blood (10 µL), reducing or eliminating the volumetric blood hematocrit assay-bias associated with the dried blood spotting technique. We developed a high-performance liquid chromatographic method with tandem mass spectrometry detection for quantification of cefepime. Sample extraction from VAMS™ devices, followed by reversed-phase chromatographic separation and selective detection using tandem mass spectrometry with a 4 min runtime per sample was employed. Standard curves were linear between 0.1-100 µg/mL for cefepime. Intra- and inter-day accuracies were within 95.4-113% and precision (CV) was < 15 % based on a 3-day validation study. Recoveries ranged from 40.8 to 62.1% and the matrix effect was within 89.5-96.7% for cefepime. Cefepime was stable in human whole blood under assay conditions (3 h at room temperature, 24 h in autosampler post-extraction). Cefepime was also stable for at least 1 week (7 days) at 4 °C, 1 month (39 days) at -20 °C and 3 months (91 days) at -78 °C as dried microsamples. This assay provides an efficient quantitation of cefepime and was successfully implemented for the analysis of whole blood microsamples in a pediatric clinical trial.

Morphine Dose Optimization in Critically Ill Pediatric Patients With Acute Respiratory Failure: A Population Pharmacokinetic-Pharmacogenomic Study.

OBJECTIVE: To develop a pharmacokinetic-pharmacogenomic population model of morphine in critically ill children with acute respiratory failure. DESIGN: Prospective pharmacokinetic-pharmacogenomic observational study. SETTING: Thirteen PICUs across the United States. PATIENTS: Pediatric subjects (n = 66) mechanically ventilated for acute respiratory failure, weight greater than or equal to 7 kg, receiving morphine and/or midazolam continuous infusions. INTERVENTIONS: Serial blood sampling for drug quantification and a single blood collection for genomic evaluation. MEASUREMENTS AND MAIN RESULTS: Concentrations of morphine, the two main metabolites, morphine-3-glucuronide and morphine-6-glucuronide, were quantified by high-performance liquid chromatography tandem mass spectrometry/mass spectroscopy. Subjects were genotyped using the Illumina HumanOmniExpress genome-wide single nucleotide polymorphism chip. Nonlinear mixed-effects modeling was performed to develop the pharmacokinetic-pharmacogenomic model. A two-compartment model with linear elimination and two individual compartments for metabolites best describe morphine disposition in this population. Our analysis demonstrates that body weight and postmenstrual age are relevant predictors of pharmacokinetic parameters of morphine and its metabolites. Furthermore, our research shows that a duration of mechanical ventilation greater than or equal to 10 days reduces metabolite formation and elimination upwards of 30%. However, due to the small sample size and relative heterogeneity of the population, no heritable factors associated with uridine diphosphate glucuronyl transferase 2B7 metabolism of morphine were identified. CONCLUSIONS: The results provide a better understanding of the disposition of morphine and its metabolites in critically ill children with acute respiratory failure requiring mechanical ventilation due to nonheritable factors. It also provides the groundwork for developing additional studies to investigate the role of heritable factors.

Midazolam Dose Optimization in Critically Ill Pediatric Patients With Acute Respiratory Failure: A Population Pharmacokinetic-Pharmacogenomic Study.

OBJECTIVES: To develop a pharmacokinetic-pharmacogenomic population model of midazolam in critically ill children with primary respiratory failure. DESIGN: Prospective pharmacokinetic-pharmacogenomic observational study. SETTING: Thirteen PICUs across the United States. PATIENTS: Pediatric subjects mechanically ventilated for acute respiratory failure, weight greater than or equal to 7 kg, receiving morphine and/or midazolam continuous infusions. INTERVENTIONS: Serial blood sampling for drug quantification and a single blood collection for genomic evaluation. MEASUREMENTS AND MAIN RESULTS: Concentrations of midazolam, the 1' (1`-hydroxymidazolam metabolite) and 4' (4`-hydroxymidazolam metabolite) hydroxyl, and the 1' and 4' glucuronide metabolites were measured. Subjects were genotyped using the Illumina HumanOmniExpress genome-wide single nucleotide polymorphism chip. Nonlinear mixed effects modeling was performed to develop the pharmacokinetic-pharmacogenomic model. Body weight, age, hepatic and renal functions, and the UGT2B7 rs62298861 polymorphism are relevant predictors of midazolam pharmacokinetic variables. The estimated midazolam clearance was 0.61 L/min/70kg. Time to reach 50% complete mature midazolam and 1`-hydroxymidazolam metabolite/4`-hydroxymidazolam metabolite clearances was 1.0 and 0.97 years postmenstrual age. The final model suggested a decrease in midazolam clearance with increase in alanine transaminase and a lower clearance of the glucuronide metabolites with a renal dysfunction. In the pharmacogenomic analysis, rs62298861 and rs28365062 in the UGT2B7 gene were in high linkage disequilibrium. Minor alleles were associated with a higher 1`-hydroxymidazolam metabolite clearance in Caucasians. In the pharmacokinetic-pharmacogenomic model, clearance was expected to increase by 10% in heterozygous and 20% in homozygous for the minor allele with respect to homozygous for the major allele. CONCLUSIONS: This work leveraged available knowledge on nonheritable and heritable factors affecting midazolam pharmacokinetic in pediatric subjects with primary respiratory failure requiring mechanical ventilation, providing the basis for a future implementation of an individual-based approach to sedation.

An improved ultra-high-performance liquid chromatography-tandem mass spectrometric method for the quantitation of dexmedetomidine in small volume of pediatric plasma.

Dexmedetomidine (Dex), a highly selective α2 -adrenergic agonist, is used primarily for the sedation and anxiolysis of adults and children in the intensive care setting. A sensitive and selective assay for Dex in pediatric plasma was developed by employing ultra-high-performance liquid chromatography-tandem mass spectrometry with d4-Dex as an internal standard. Dex was extracted from 0.1 mL of plasma by micro-elution solid-phase extraction. Separation was achieved with a Waters XBridge C18 column with a flow rate of 0.3 mL/min using a mobile phase comprising 5 mm ammonium acetate buffer with 0.03% formic acid in water and methanol-acetonitrile (50:50, v/v). The intra-day precision (coefficient of variation) and accuracy for quality control samples ranged from 1.32 to 8.91% and from 92.8 to 108%, respectively. The inter-day precision and accuracy ranged from 2.13 to 8.45% and from 97.0 to 104%, respectively. The analytical method showed excellent sensitivity using a small sample volume (0.1 mL) with a lower limit of quantitation of 5 pg/mL. This method is robust and has been successfully employed in a pharmacokinetic study of Dex in neonates and infants postoperative from cardiac surgery.

Development and validation of a volumetric absorptive microsampling assay for analysis of voriconazole and voriconazole N-oxide in human whole blood.

Voriconazole is a broad-spectrum antifungal triazole drug for the treatment of invasive fungal infections. It is extensively metabolized by hepatic drug metabolizing enzymes cytochrome (CYP) 2C19 and CYP3A4. Selective inhibition of intestinal CYP3A4 by grapefruit juice may increase the oral bioavailability of voriconazole in children. To test this hypothesis it is necessary to develop a sensitive assay for measuring voriconazole and its major metabolites in a small volume of blood. Mitra® devices from Neoteryx were employed to develop and validate the assay for the quantitation of voriconazole and voriconazole N-oxide. Mitra® devices utilize volumetric absorptive microsampling (VAMS™) technology that enables accurate and precise collection of a fixed volume (10 µL of blood), reducing or eliminating the volumetric blood hematocrit assay-bias associated with the dried blood spotting technique. We developed an ultra-performance liquid chromatographic method with tandem mass spectrometry detection for quantification of voriconazole and voriconazole N-oxide. Sample extraction of Mitra® devices, followed by reversed-phase chromatographic separation and selective detection using tandem mass spectrometry with a 4.00 minute runtime per sample was employed. Standard curves were linear between 10.0 to 10,000 ng/mL for both voriconazole and voriconazole N-oxide. Intra- and inter-day accuracy were within 87-102% and precision (CV) was <12% based on a 3-day validation study. Recoveries were ≥94 % for voriconazole and ≥87 % for voriconazole N-oxide. Voriconazole and voriconazole N-oxide were stable in human whole blood under assay conditions (19 h at room temperature and 24 h in autosampler). Voriconazole was stable for 1-month in dried microsamples under different conditions (4, -20 and -78 °C). This assay provides an efficient quantitation of voriconazole and voriconazole N-oxide and is ready to be implemented for the analysis of whole blood microsamples in a pediatric clinical trial investigating the impact of intestinal inhibition of CYP3A4 on voriconazole pharmacokinetics.

Use of Intravenous Acetaminophen in Children for Analgesia After Spinal Fusion Surgery: A Randomized Clinical Trial.

OBJECTIVES: Opioid pharmacotherapy is the cornerstone of postoperative analgesia. Despite its effectiveness, it has a variety of potential adverse effects. Therefore, a multimodal approach with non-opioid analgesics would be optimal. The aim of this study was to determine if intravenous (IV) acetaminophen would reduce opioid requirements and improve clinical outcomes in children after surgery. METHODS: A single-center, randomized, double-blind study was conducted in 57 children (10-18 years old) undergoing posterior spine fusion surgery between July 2011 to May 2014. All subjects received either acetaminophen or placebo at the end of surgery, followed by repeated doses every 6 hours for a total of 8 doses. RESULTS: In the first 24 postoperative hours, the average opioid consumption was lower for the active group compared with the placebo group (p = 0.02). The total unadjusted time to patient controlled analgesia (PCA) discontinuation was also longer in the placebo group than the active group (90 hours vs. 73 hours, p = 0.02); however, this was not statistically significant after normalizing for body weight. Additionally, time to first solid intake was longer without the use of acetaminophen (69 hours vs. 49 hours, p = 0.01). CONCLUSIONS: Postoperative use of IV acetaminophen was associated with earlier time to diet advancement and discontinuation of IV analgesics and may result in lower opioid consumption.