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Su F.,Childrens Hospital of Philadelphia | Gastonguay M.R.,Metrum Institute | Nicolson S.C.,Childrens Hospital of Philadelphia | Diliberto M.,Childrens Hospital of Philadelphia | And 2 more authors.
Anesthesia and Analgesia | Year: 2016

Background: Dexmedetomidine is a highly selective α2-agonist with hypnotic, analgesic, and anxiolytic properties. Despite off-label administration, dexmedetomidine has found a niche in critically ill neonates and infants with congenital heart disease because of its minimal effects on respiratory function at sedative doses, facilitating early extubation and fast-track postoperative care. There are little pharmacokinetic data regarding newborns who have immature drug metabolizing capacity and who are at risk for reduced dexmedetomidine clearance and drug toxicity. The aim of this study was to determine the pharmacokinetics of dexmedetomidine in neonates and infants after open heart surgery. This study included 23 evaluable neonates (age, 1 day-1 month) and 36 evaluable infants (age, 1 month-24 months) after open heart surgery. Methods: Full-term neonates and infants requiring mechanical ventilation after open heart surgery received dexmedetomidine in a dose-escalation study. Dexmedetomidine was administered as a loading dose over 10 minutes followed by a continuous IV infusion up to 24 hours. Cohorts of 12 infants were enrolled sequentially to receive 0.35, 0.7, or 1 μg/kg dexmedetomidine followed by 0.25, 0.5, or 0.75 μg/kg/h dexmedetomidine, respectively. Cohorts of 9 neonates received 0.25, 0.35, or 0.5 μg/kg dexmedetomidine followed by 0.2, 0.3, or 0.4 μg/kg/h dexmedetomidine, respectively. Plasma dexmedetomidine concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A population nonlinear mixed effects modeling approach was used to characterize dexmedetomidine pharmacokinetics. Results: Pharmacokinetic parameters of dexmedetomidine were estimated using a 2-compartment disposition model with weight allometrically scaled as a covariate on drug clearance, intercompartmental clearance, central and peripheral volume of distributions and age, total bypass time, and intracardiac shunting on clearance. Dexmedetomidine demonstrated a plasma drug clearance of 657 × (weight/70)0.75 mL/min, intercompartmental clearance of 6780 × (weight/70)0.75 mL/min, central volume of distribution of 88 × (weight/70) L and peripheral volume of distribution of 112 × (weight/70) L for a typical subject with age >1 month with a cardiopulmonary bypass time of 60 minutes and without right-to-left intracardiac shunt. Dexmedetomidine pharmacokinetics may be influenced by age during the neonatal period, weight, total bypass time, and presence of intracardiac shunt. Conclusions: Dexmedetomidine clearance is significantly diminished in full-term newborns and increases rapidly in the first few weeks of life. The dependence of clearance on age during the first few weeks of life reflects the relative immaturity of metabolic processes during the newborn period. Continuous infusions of up to 0.3 μg/kg/h in neonates and 0.75 μg/kg/h in infants were well tolerated after open heart surgery. © 2016 International Anesthesia Research Society.

Mascarenhas M.R.,Childrens Hospital of Philadelphia | Mondick J.,Metrum Institute | Barrett J.S.,University of Pennsylvania | Barrett J.S.,Sanofi S.A. | And 2 more authors.
Journal of Clinical Pharmacology | Year: 2015

The malabsorption blood test (MBT), consisting of pentadecanoic acid (PA), a free fatty acid, and triheptadecanoic acid (THA), a triglyceride that requires pancreatic lipase for absorption of the heptadecanoic acid (HA), was developed to assess fat malabsorption in patients with cystic fibrosis (CF) and pancreatic insufficiency (PI). The objective was to construct a population pharmacokinetic (PK) model to describe PA and HA disposition in healthy subjects and CF subjects. A model was simultaneously fit to PA and HA concentrations, consisting of 1-compartment disposition and a transit model to describe absorption. PA bioavailability estimates for CF subjects without pancreatic enzyme administration (1.07 [0.827, 1.42]) and with enzymes (0.88 [0.72, 1.09]) indicated PA absorption comparable to healthy subjects. HA bioavailability in CF without enzyme administration was 0.0292 (0.0192, 0.0459) and with enzymes increased to 0.606 (0.482, 0.823). In CF, compared with taking enzymes with the MBT, HA bioavailability was further decreased by factors of 0.829 (0.664, 0.979) and 0.78 (0.491, 1.13) with enzymes taken 30 and 60 minutes after MBT, respectively. The MBT detected differences in fat absorption in subjects with CF with and without enzyme administration and with changes in enzyme timing. Future studies will address application of the MBT in CF and other malabsorption diagnoses. © 2015, The American College of Clinical Pharmacology.

Stricker P.A.,Childrens Hospital of Philadelphia | Gastonguay M.R.,Metrum Institute | Singh D.,Childrens Hospital of Philadelphia | Fiadjoe J.E.,Childrens Hospital of Philadelphia | And 4 more authors.
British Journal of Anaesthesia | Year: 2015

Background Despite demonstrated efficacy of ε-aminocaproic acid (EACA) in reducing blood loss in adolescents undergoing spinal fusion, there are no population-specific pharmacokinetic data to guide dosing. The aim of this study was to determine the pharmacokinetics of EACA in adolescents undergoing spinal fusion surgery and make dosing recommendations. Methods Twenty children ages 12-17 years were enrolled, with 10 children in each of two groups based on diagnosis (idiopathic scoliosis or non-idiopathic scoliosis). Previously reported data from infants undergoing craniofacial surgery were included in the model to enable dosing recommendations over a wide range of weights, ages, and diagnoses. A population non-linear mixed effects modelling approach was used to characterize EACA pharmacokinetics. Results Population pharmacokinetic parameters were estimated using a two-compartment disposition model with allometrically scaled weight and an age effect on clearance. Pharmacokinetic parameters for the typical patient were a plasma clearance of 153 ml min-1 70 kg-1 (6.32 ml min-1 kg-0.75), intercompartmental clearance of 200 ml min-1 70 kg-1 (8.26 ml min-1 kg-0.75), central volume of distribution of 8.78 litre 70 kg-1 (0.13 litre kg-1), and peripheral volume of distribution of 15.8 litre 70 kg-1 (0.23 litre kg-1). Scoliosis aetiology did not have a clinically significant effect on drug pharmacokinetics. Conclusions The following dosing schemes are recommended according to patient weight: weight <25 kg, 100 mg kg-1 loading dose and 40 mg kg-1 h-1 infusion; weight ≤25 kg-<50 kg, 100 mg kg-1 loading dose and 35 mg kg-1 h-1 infusion; and weight ≥50 kg, 100 mg kg-1 loading dose and 30 mg kg-1 h-1 infusion. An efficacy trial employing this dosing strategy is warranted. Clinical trial registration NCT01408823. © 2015 The Author.

Rovner A.J.,Childrens Hospital of Philadelphia | Schall J.I.,Childrens Hospital of Philadelphia | Mondick J.T.,Metrum Institute | Zhuang H.,Childrens Hospital of Philadelphia | Mascarenhas M.R.,Childrens Hospital of Philadelphia
Journal of Pediatric Gastroenterology and Nutrition | Year: 2013

OBJECTIVE: Gastrointestinal disturbances are common in people with cystic fibrosis (CF); however, motility studies in this population have yielded inconsistent results. This study examined gastric emptying (GE) and small bowel transit (SBT) time in children with CF and pancreatic insufficiency compared with a healthy adult reference group. METHODS: Participants consumed an 8-ounce liquid test meal (approximately 550 calories, 32 g of fat) labeled with 300 μCi 99m technetium (Tc) sulfur colloid. Subjects with CF received a standard dose of pancreatic enzymes before consuming the test meal. GE and SBT were measured using a standard nuclear medicine scan. GE was determined after correcting for 99mTc decay in both anterior and posterior images. SBT was determined by following the movement of the tracer from the stomach to the cecum. The percentage arrival of total small bowel activity at the terminal ileum and cecum/ascending colon at 6 hours was used as an index of SBT. A 1-way analysis of covariance was performed for comparisons between groups after adjustment for age, sex, and body mass index. RESULTS: Subjects with CF (n=16) had similar GE compared with the healthy reference group (n=12); however, subjects with CF had significantly prolonged SBT time. At 6 hours, 37.2%±25.4% (95% CI 23.7-50.7) of the tracer reached the terminal ileum and colon compared with 68.6%±13.1% (95% CI 60.2-76.9) for the reference group (P<0.001). After controlling for sex, age, and body mass index, this difference remained statistically significant (F=12.06, adjusted R 2=0.44, P<0.002). CONCLUSIONS: Children with CF and pancreatic insufficiency had unaltered GE but delayed SBT time when taking pancreatic enzymes. Copyright © 2013 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Mondick J.T.,Metrum Institute | Johnson B.M.,Glaxosmithkline | Haberer L.J.,Glaxosmithkline | Sale M.E.,Next Level Solutions | And 6 more authors.
European Journal of Clinical Pharmacology | Year: 2010

Purpose: Until recently, ondansetron was approved for the prevention of nausea and vomiting only in patients older than 2 years. However, as the use of ondansetron in patients younger than 2 years had been documented, characterization of ondansetron pharmacokinetics in this younger pediatric age group was warranted. Methods: The pharmacokinetics of intravenously administered ondansetron were evaluated in oncology and surgical patients aged 1-48 months. Pooled data from 124 patients, including 745 pharmacokinetic samples, were analyzed using nonlinear mixed-effects modeling. Results: Ondansetron pharmacokinetics were described by a two-compartment model. Body-size effects on ondansetron disposition were accounted for via standard allometric relationships, normalized to 10.4 kg. A maturation process with a half-life of approximately 4 months was incorporated to describe a decrease in clearance (CL) in infants. Clearance [95% confidence interval (CI)] for a typical patient was 1.53 (1.34-1.78) L/h/kg0.75 with an interindividual variability of 56.8%. Ondansetron CL was reduced by 31%, 53%, and 76% for the typical 6-month-, 3-month-, and 1-month-old patient, respectively. Simulations showed that an ondansetron dose of 0.1 mg/kg in children younger than 6 months produced exposure similar to a 0.15-mg/kg dose in older children. Conclusions: The population pharmacokinetic analysis of ondansetron allows for characterization of individual patients based on body weight and age. It is recommended that patients younger than 4 months receiving ondansetron be closely monitored. © 2009 Springer-Verlag.

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