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Su F.,Stanford University | Nicolson S.C.,Children's Hospital of Philadelphia | Gastonguay M.R.,Metrum Institute | Kang D.S.,Children's Hospital of Philadelphia | And 2 more authors.
Anesthesia and Analgesia | Year: 2010

Background: Dexmedetomidine is a highly selective α2- agonist with hypnotic, analgesic, and anxiolytic properties. In adults, it provides sedation while preserving respiratory function facilitating extubation. Only limited pharmacokinetic data are available for pediatric patients. The primary aim of this study was to determine the pharmacokinetics of dexmedetomidine in infants after open heart surgery. Methods: We evaluated 36 infants, aged 1 to 24 months, after open heart surgery. Cohorts of 12 infants requiring mechanical ventilation after open heart surgery were enrolled sequentially to 1 of the 3 initial loading dose-continuous IV infusion (CIVI) regimens: 0.35-0.25, 0.7-0.5, or 1-0.75 μg/kg-μg/kg/h. The initial loading dose was administered over 10 minutes immediately postoperatively followed by a CIVI of up to 24 hours. 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 on drug clearance, intercompartmental clearance, central and peripheral volume of distributions, total bypass time as a covariate on clearance and central volume of distribution, and age and ventricular physiology as covariates on clearance. Infants demonstrated a clearance of 28.1 mL/min/kg0.75, intercompartmental clearance of 93.4 mL/min/kg 0.75, central volume of distribution of 1.2 L/kg, and peripheral volume of distribution of 1.5 L/kg. Conclusions: Dexmedetomidine clearance increased with weight, age, and single-ventricle physiology, whereas total bypass time was associated with a trend toward decreasing clearance, and central volume of distribution increased as a function of total bypass time. The dependence of clearance on body weight supports current practice of weight-based dexmedetomidine dosing, whereas the clinical impact of the remaining covariate effects requires further investigation. Initial loading doses in the range of 0.35 to 1 μg/kg over 10 minutes and CIVI of 0.25 to 0.75 μg/kg/h were well tolerated in this infant population. Copyright © 2010 International Anesthesia Research Society.


PubMed | University of Pennsylvania, Children's Hospital of Philadelphia and Metrum Institute
Type: Controlled Clinical Trial | Journal: 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.


Su F.,Children's Hospital of Philadelphia | Gastonguay M.R.,Metrum Institute | Nicolson S.C.,Children's Hospital of Philadelphia | Diliberto M.,Children's 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.


Clark A.M.,University of Minnesota | Clark A.M.,Upsher Smith Laboratories Inc. | Mondick J.T.,Metrum Institute | Cloyd J.C.,University of Minnesota | And 3 more authors.
Pediatric Research | Year: 2013

Background: Cerebral white matter (WM) injury and stroke are common neuropathological injuries in newborns with congenital heart defects (CHDs) requiring surgery. Previous investigations in Long Evans rat pups subjected to hypoxia-ischemia found that intraperitoneal (i.p.) topiramate (TPM) at 30 mg/kg, but not 50 mg/kg, conferred neuroprotection. In Sprague-Dawley pups, a dose of 30 mg/kg protected against stroke. Concentrations associated with neuroprotective doses were not measured. The aims of this investigation were to determine concentrations associated with neuroprotective doses and to investigate the pharmacokinetics (PK) of i.p. TPM.Methods:Concentration-time data following administration of 30 and 50 mg/kg doses were analyzed using nonlinear mixed-effect modeling.Results:Mean predicted steady-state maximum and average concentrations following 30 mg/kg TPM were 31.3 and 16.8 μg/ml in Long Evans and 39.9 and 24.4 μg/ml in Sprague-Dawley pups. Mean predicted steady-state maximum and average concentrations following 50 mg/kg TPM were 52.1 and 28.1 μg/ml in Long Evans and 66.5 and 40.6 μg/ml in Sprague-Dawley pups. The apparent clearance (CL/F) and apparent volume of distribution (V/F) were 0.0470 ml/min and 22.2 ml, respectively, for Long Evans and 0.0325 ml/min and 19.7 ml, respectively, for Sprague-Dawley pups.Conclusion:TPM concentrations associated with neuroprotective doses were determined. Body size and strain were significant covariates on CL/F and V/F. Results provide targets for future neuroprotection studies. Copyright © 2013 International Pediatric Research Foundation, Inc.


Bergsma T.T.,Metrum Institute | Knebel W.,Metrum Institute | Fisher J.,Metrum Institute | Gillespie W.R.,Metrum Institute | And 3 more authors.
Computer Methods and Programs in Biomedicine | Year: 2013

metrumrg is an R package that facilitates workflow for the discipline of pharmacometrics. Support is provided for data preparation, modeling, simulation, diagnostics, and reporting. Existing tools and techniques are emphasized where available; original solutions are provided for otherwise unmet needs. In particular, metrumrg implements an R interface for the NONMEM® modeling software, optionally run in a distributed computing environment. The paradigm allows start-to-finish analyses in a single scripting language. Emphasis on text-based formats promotes traceability of results. © 2012 Elsevier Ireland Ltd.


Stricker P.A.,Children's Hospital of Philadelphia | Gastonguay M.R.,Metrum Institute | Singh D.,Children's Hospital of Philadelphia | Fiadjoe J.E.,Children's 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.,Children's Hospital of Philadelphia | Schall J.I.,Children's Hospital of Philadelphia | Mondick J.T.,Metrum Institute | Zhuang H.,Children's Hospital of Philadelphia | Mascarenhas M.R.,Children's 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.


Zuppa A.F.,Children's Hospital of Philadelphia | Nicolson S.C.,Children's Hospital of Philadelphia | Barrett J.S.,Metrum Institute | Gastonguay M.R.,Metrum Institute
Journal of Pediatrics | Year: 2011

Objectives: To determine the pharmacokinetics of pentobarbital in neonates, infants, and young children with congenital heart disease after open-heart surgery. Study design: Thirty-five subjects (3.0 days-4.4 years) after open-heart surgery who received pentobarbital as standard of care were enrolled. Serial pharmacokinetic blood samples were obtained. A population-based, nonlinear mixed-effects modeling approach was used to characterize pentobarbital pharmacokinetics. Results: A two-compartment model with weight as a co-variate allometrically expressed on clearance (CL), inter-compartmental clearance, central (V1) and peripheral volume of distributions, bypass grafting time as a co-variate on CL and V1, and age and ventricular physiology as co-variates on CL best described the pharmacokinetics. A typical infant (two-ventricle physiology, 6.9 kg, 5.2 months, and bypass grafting time of 60 minutes) had a CL of 0.12 L/hr/kg, V1 of 0.45 L/kg, and peripheral volume of distributions of 0.98 L/kg. The bypass grafting effect was poorly estimated. For subjects <12 months age, an age effect on CL remained after accounting for weight and was precisely estimated. Conclusions: Pentobarbital pharmacokinetics is influenced by age and weight. Subjects with single-ventricle physiology demonstrated a 15% decrease in clearance when compared with subjects with two-ventricle physiology. © 2011 Mosby Inc. All rights reserved.


PubMed | Children's Hospital of Philadelphia and Metrum Institute
Type: Clinical Trial | Journal: British journal of anaesthesia | Year: 2015

Despite demonstrated efficacy of -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.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.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.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.NCT01408823.


Stricker P.A.,Children's Hospital of Philadelphia | Zuppa A.F.,Children's Hospital of Philadelphia | Fiadjoe J.E.,Children's Hospital of Philadelphia | Maxwell L.G.,Children's Hospital of Philadelphia | And 7 more authors.
British Journal of Anaesthesia | Year: 2013

BackgroundUnderstanding the clinical pharmacology of the antifibrinolytic epsilon-aminocaproic acid (EACA) is necessary for rational drug administration in children. The aim of this study is to determine the pharmacokinetics (PKs) of EACA in infants aged 6-24 months undergoing craniofacial reconstruction surgery.MethodsCohorts of six infants were enrolled sequentially to one of the three escalating loading dose-continuous i.v. infusion (CIVI) regimens: 25 mg kg-1, 10 mg kg-1 h-1; 50 mg kg-1, 20 mg kg-1 h-1; 100 mg kg-1, 40 mg kg -1 h-1. Plasma EACA concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A population non-linear mixed effects modelling approach was used to characterize EACA PKs.ResultsPopulation PK parameters of EACA were estimated using a two-compartment disposition model with weight expressed as an allometric covariate and an age effect. The typical patient in this study had an age of 38.71 weeks and a weight of 8.82 kg. PK parameters for this typical patient were: pre-/postoperative plasma drug clearance of 32 ml min-1 (3.6 ml kg-1 min-1), inter-compartmental clearance of 42.4 ml min-1 (4.8 ml min-1 kg-1), central volume of distribution of 1.27 litre (0.14 litre kg-1), and peripheral volume of distribution of 2.53 litre (0.29 litre kg-1). Intra-operative clearance and central volume of distribution were 89% and 80% of the pre-/postoperative value, respectively.ConclusionsEACA clearance increased with weight and age. The dependence of clearance on body weight supports weight-based dosing. Based on this study, a loading dose of 100 mg kg-1 followed by a CIVI of 40 mg kg-1 h-1 is appropriate to maintain target plasma EACA concentrations in children aged 6-24 months undergoing these procedures. © 2013 Author.

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