Luis M. Pereira

Efficacy of Tranexamic Acid in Pediatric Craniosynostosis Surgery: A Double-blind, Placebo-controlled Trial

Background:Extensive blood loss is common in pediatric craniosynostosis reconstruction surgery. Tranexamic acid (TXA) is increasingly used to reduce perioperative blood loss in various settings, but data on its efficacy are limited in children. The purpose of this randomized, double-blind, placebo-controlled, parallel trial was to evaluate the efficacy of TXA in pediatric craniosynostosis correction surgery. The primary and secondary outcome variables were reduction in perioperative blood loss and reduction in blood transfusion, respectively. Methods:Forty-three children, ages 2 months to 6 yr, received either placebo or TXA in a loading dose of 50 mg·kg−1, followed by an infusion of 5 mg·kg−1·h−1 during surgery. TXA plasma concentrations were measured. Results:The TXA group had significantly lower perioperative mean blood loss (65 vs. 119 ml·kg−1, P < 0.001) and lower perioperative mean blood transfusion (33 vs. 56 ml· kg−1, P = 0.006) compared to the placebo group. The mean difference between the TXA and placebo groups for total blood loss was 54 ml·kg−1 (95% CI for the difference, 23–84 ml·kg−1) and for packed erythrocytes transfused was 23 ml·kg−1 (95% CI for the difference, 7–39 ml·kg−1). TXA administration also significantly diminished (by two thirds) the perioperative exposure of patients to transfused blood (median, 1 unit vs. 3 units; P < 0.001). TXA plasma concentrations were maintained above the in vitro thresholds reported for inhibition of fibrinolysis (10 &mgr;g·ml−1) and plasmin-induced platelet activation (16 &mgr;g·ml−1) throughout the infusion. Conclusions:TXA is effective in reducing perioperative blood loss and transfusion requirement in children undergoing craniosynostosis reconstruction surgery.

Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome

Significance This paper provides unique insights into mechanism-based therapeutics for Rett syndrome (RTT), a devastating neurodevelopmental disorder. This clinical trial was based on pioneer preclinical work from the laboratory of M.S. Outcome measures include clinical instruments, standardized behavioral measures, and biomarkers, the latter being not only objective but also applicable to experimental studies. We believe this work will a have major impact on the understanding and treatment of RTT, as well as other neurodevelopmental disorders. Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40–120 μg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.

Deferasirox pharmacokinetics in patients with adequate versus inadequate response

Tens of thousands of transfusion-dependent (eg, thalassemia) patients worldwide suffer from chronic iron overload and its potentially fatal complications. The oral iron chelator deferasirox has become commercially available in many countries since 2006. Although this alternative to parenteral deferoxamine has been a major advance for patients with transfusional hemosiderosis, a proportion of patients have suboptimal response to the maximum approved doses (30 mg/kg per day), and do not achieve negative iron balance. We performed a prospective study of oral deferasirox pharmacokinetics (PK), comparing 10 transfused patients with inadequate deferasirox response (rising ferritin trend or rising liver iron on deferasirox doses > 30 mg/kg per day) with control transfusion-dependent patients (n = 5) with adequate response. Subjects were admitted for 4 assessments: deferoxamine infusion and urinary iron measurement to assess readily chelatable iron; quantitative hepatobiliary scintigraphy to assess hepatic uptake and excretion of chelate; a 24-hour deferasirox PK study following a single 35-mg/kg dose of oral deferasirox; and pharmacogenomic analysis. Patients with inadequate response to deferasirox had significantly lower systemic drug exposure compared with control patients (P < .00001). Cmax, volume of distribution/bioavailability (Vd/F), and elimination half-life (t(1/2)) were not different between the groups, suggesting bioavailability as the likely discriminant. Effective dosing regimens for inadequately responding patients to deferasirox must be determined. This trial has been registered at http://www.clinicaltrials.gov under identifier NCT00749515.

Effect of Weight and Maturation on Busulfan Clearance in Infants and Small Children Undergoing Hematopoietic Cell Transplantation

Little information is currently available regarding the pharmacokinetics (PK) of busulfan in infants and small children to help guide decisions for safe and efficacious drug therapy. The objective of this study was to develop an algorithm for individualized dosing of i.v. busulfan in infants and children weighing ≤12 kg, that would achieve targeted exposure with the first dose of busulfan. Population PK modeling was conducted using intensive time-concentration data collected through the routine therapeutic drug monitoring of busulfan in 149 patients from 8 centers. Busulfan PK was well described by a 1-compartment base model with linear elimination. The important clinical covariates affecting busulfan PK were actual body weight and age. Based on our model, the predicted clearance of busulfan increases approximately 1.7-fold between 6 weeks to 2 years of life. For infants age <5 months, the model-predicted doses (mg/kg) required to achieve a therapeutic concentration at steady state of 600-900 ng/mL (area under the curve range, 900-1350 μM·min) were much lower compared with standard busulfan doses of 1.1 mg/kg. These results could help guide clinicians and inform better dosing decisions for busulfan in young infants and small children undergoing hematopoietic cell transplantation.

Pharmacokinetics of Tranexamic Acid in Neonates, Infants, and Children Undergoing Cardiac Surgery with Cardiopulmonary Bypass

Background:Tranexamic acid (TXA) is one of the most commonly used antifibrinolytic medications in children undergoing repair of congenital heart defects. However, a pharmacokinetics analysis of TXA has never been performed in neonates or young children undergoing complex cardiac surgeries using cardiopulmonary bypass, hypothermia, circulatory arrest, and ultrafiltration. A comprehensive pharmacokinetics study was performed in this patient population. Methods:Fifty-five patients ranging from 2 days through 4 yr old were categorized into three groups: children less than 2 months old, infants 2 months to 1 yr old, and children greater than 1 yr old and weighing up to 20 kg. TXA was given as a bolus of 100 mg/kg followed by an infusion of 10 mg · kg−1 · h−1 throughout the surgery. A dose of 100 mg/kg was placed in the cardiopulmonary bypass prime. A total of 16 to 18 samples were obtained from all patients throughout surgery. Plasma TXA concentrations were measured by high-performance liquid chromatography and modeled under a nonlinear mixed-effects framework with a two-compartment structural model. Results:Cardiopulmonary bypass had a statistically significant impact on all pharmacokinetic parameters. Age was a better covariate than body weight, affecting both the distribution and the elimination of TXA. However, weight performed well in some cases. Other covariates including body surface area, pump prime volume, ultrafiltrate volume, and body temperature did not improve the model. Conclusions:This TXA pharmacokinetic analysis is reported for the first time in neonates and young children undergoing complex cardiac surgeries with cardiopulmonary bypass. Dosing recommendations are provided as guidance for maintaining desired target concentrations.

Effect of Excipients on Acetaminophen Metabolism and Its Implications for Prevention of Liver Injury

Acetaminophen poisoning is the most frequent cause of acute hepatic failure in the US. Toxicity requires reductive metabolism of acetaminophen, primarily via CYP2E1. Liquid acetaminophen preparations contain propylene glycol, a common excipient that has been shown to reduce hepatocellular injury in vitro and in rodents. Children are less susceptible to acetaminophen toxicity for unclear reasons. We conducted a pharmacokinetic single‐blinded crossover study of 15 healthy adult volunteers comparing the CYP2E1 and conjugative metabolism of a 15 mg/kg dose of liquid versus solid preparations of acetaminophen. Measured AUCs for the CYP2E1 metabolites were 16–17% lower and extrapolated AUCs were 25–28% lower in the liquid formulation arm while there was no difference in conjugative metabolite production. The formation rate constants for reductive metabolites were equivalent between solid and liquid formulations indicating that enzyme inhibition was competitive. Propylene glycol, an established CYP2E1 competitive antagonist, was detected in the liquid formulation but not solid formulation arm. Since children tend to ingest liquid preparations, the protective effect of this excipient could explain their decreased susceptibility to acetaminophen toxicity. A less hepatotoxic formulation of acetaminophen could potentially be developed if co‐formulated with a CYP2E1 inhibitor.

Experimental model of hyperfibrinolysis designed for rotational thromboelastometry in children with congenital heart disease.

We assessed an in-vitro model of hyperfibrinolysis using rotational thromboelastometry (ROTEM) by the addition of increasing concentrations of tissue-type plasminogen activator (t-PA) on whole blood obtained from children undergoing cardiac surgery. We assessed the relevance of this model by repeating the tests in the same population after tranexamic acid (TXA) infusion. In addition, we determined the sensitivity and specificity of ROTEM parameters to detect the different degrees of fibrinolysis. Blood samples obtained from 20 children were analyzed at two predefined timepoints: after induction of anesthesia, before TXA (baseline), and at the end of surgery during TXA infusion (end surgery). At baseline, an extrinsic activation with tissue factor (EXTEM) test was performed without and with increasing concentration of t-PA (102, 255, 512, 1024, 1535, and 2539 units t-PA/ml). At the end of surgery, a second EXTEM test was performed without and with two different t-PA concentrations (1535 and 2539 units t-PA/ml). At baseline, increasing t-PA concentrations in the EXTEM test induced a gradual increase of hyperfibrinolysis characterized by a reduction in clot firmness and stability parameters. In the presence of TXA, t-PA-induced hyperfibrinolysis was completely abolished. Lysis-onset time (LOT) and degree of fibrinolysis measured at 30 min (LI30) best assessed the degree of fibrinolysis. This in-vitro model of t-PA-induced hyperfibrinolysis using the EXTEM test of ROTEM may represent a promising tool to assess hyperfibrinolysis in the pediatric population. In addition, we observed that LOT and LI30 should be considered as the best parameters to detect different degrees of fibrinolysis.

Characterization of Ribavirin Aerosol With Small Particle Aerosol Generator and Vibrating Mesh Micropump Aerosol Technologies

BACKGROUND: Ribavirin is an antiviral drug that can be administered by inhalation. Despite advancements in the oral delivery of this medication, there has been a renewed interested in delivering ribavirin via the pulmonary system. Although data are not conclusive that inhaled ribavirin improves outcomes, we set out to determine whether delivery by a newer generation nebulizer, the vibrating mesh micropump, was as effective as the recommended small-particle aerosol generator system. METHODS: We compared the physicochemical makeup and concentrations of ribavirin before and after nebulization with 0.9% NaCl and sterile water. An Andersen cascade impactor was used to determine particle size distribution and mass median aerodynamic diameter, and an absolute filter was used to measure total aerosol emitted output and inhaled dose during mechanical ventilation and spontaneous breathing. Ribavirin was analyzed and quantified using high-performance liquid chromatography with tandem mass spectrometric detection. RESULTS: Ribavirin was found to be stable in both 0.9% aqueous NaCl and sterile water with an r2 value of 0.96 and identical coefficients of variation with no difference in drug concentration before and after nebulization with the vibrating mesh micropump. The small-particle aerosol generator produced a smaller mass median aerodynamic diameter (1.84 μm) than the vibrating mesh micropump (3.63 μm, P = .02); however, there was no significant difference in the proportion of drug mass in the 0.7–4.7-μm particle range. Total drug delivery was similar with the small-particle aerosol generator and vibrating mesh micropump in both spontaneously breathing (P = .77) and mechanical ventilation (P = .48) models. CONCLUSIONS: The vibrating mesh micropump nebulizer may provide an effective alternative to the small-particle aerosol generator in administration of ribavirin using NaCl or sterile water, both on and off the ventilator. Further clinical studies are needed to compare efficacy.

Gastric Emptying in Critically Ill Children.

Background: Delayed gastric emptying (GE) impedes enteral nutrient (EN) delivery in critically ill children. We examined the correlation between (a) bedside EN intolerance assessments, including gastric residual volume (GRV); (b) delayed GE; and (c) delayed EN advancement. Materials and Methods: We prospectively enrolled patients ≥1 year of age, eligible for gastric EN and without contraindications to acetaminophen. Gastric emptying was determined by the acetaminophen absorption test, specifically the area under the curve at 60 minutes (AUC60). Slow EN advancement was defined as delivery of <50% of the prescribed EN 48 hours after study initiation. EN intolerance assessments (GRV, abdominal distension, emesis, loose stools, abdominal discomfort) were recorded. Results: We enrolled 20 patients, median 11 years (4.4–15.5), 50% male. Sixteen (80%) patients had delayed GE (AUC60 <600 mcg·min/mL) and 7 (35%) had slow EN advancement. Median GRV (mL/kg) for patients with delayed vs normal GE was 0.43 (0.113–2.188) vs 0.89 (0.06–1.91), P = .9635. Patients with slow vs rapid EN advancement had median GRV (mL/kg) of 1.02 mL/kg (0.20–3.20) vs 0.27 mL/kg (0.06–1.62), P = .3114, and frequency of altered EN intolerance assessments of 3/7 (42.9%) vs 5/13 (38.5%), P = 1. Median AUC60 for patients with slow vs rapid EN advancement was 91.74 mcg·min/mL (53.52–143.1) vs 449.5 mcg·min/mL (173.2–786.5), P = .0012. Conclusions: A majority of our study cohort had delayed GE. Bedside EN intolerance assessments, particularly GRV, did not predict delayed GE or rate of EN advancement. Delayed gastric emptying predicted slow EN advancement. Novel tests for delayed GE and EN intolerance are needed.

Bioequivalence testing by statistical shape analysis

Bioequivalence testing has been traditionally centered in summary variables such as AUC, Cmax and tmax which filter out the intrinsic information conveyed by discrete sequential concentration–time observations. Comparing entire concentration–time profiles between test and reference formulations for bioequivalence purposes provides stronger evidence about either their similarity or their discrepancy. The Kullback–Leibler information criterion (KLIC) may be computed for each concentration–time across all subjects between formulations of the same drug, with a standard crossover study design. It has been shown that if properly scaled it follow a chi-squared distribution and dependent p-values may be computed in order to construct a bioequivalence criterion. Extensive simulations and real data were used to compare it with the current standard procedures. This statistical shape analysis method may provide important clinical and regulatory advantages.