External Evaluation of Two Pediatric Population Pharmacokinetics Models of Oral Trimethoprim and Sulfamethoxazole

The antibiotic combination trimethoprim (TMP)-sulfamethoxazole (SMX) has a broad spectrum of activity and it is used for the treatment of numerous infections, but pediatric pharmacokinetic (PK) data are limited. We previously published population PK (popPK) models of oral TMP-SMX in pediatric patients based on sparse opportunistically collected data (POPS study, Antimicrob Agents Chemother 62:e01813-17, 2017, https://doi.org/10.1128/AAC.01813-17). We performed a separate PK study of oral TMP-SMX in infants and children with more traditional PK sample collection, and independently developed new popPK models of TMP-SMX using this external dataset. The POPS dataset and the External dataset were each used to evaluate both popPK models. The External TMP model had identical model and error structure as the POPS TMP model with typical values for PK parameters within 20%. The External SMX model did not identify the covariates in the POPS SMX model as significant. The External popPK models predicted higher exposures of TMP (median overprediction of 0.13 mg/L for the POPS dataset and 0.061 mg/L for the External dataset) and SMX (median overprediction of 1.7 mg/L and 0.90 mg/L) than the POPS TMP (median underprediction of 0.016 mg/L and 0.39 mg/L) and SMX (median underprediction of 1.2 mg/L and 14 mg/L) models. Nonetheless, both models supported TMP-SMX dose increases in infants and young children for more resistant pathogens with a minimum inhibitory concentration of 1 mg/L, although the required dose increase based on the External model is lower.

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A Population Pharmacokinetic Model for Vancomycin in Pediatric Patients and Its Predictive Value in a Naive Population

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.44.2.278-282.2000 ◽

2000 ◽

Vol 44 (2) ◽

pp. 278-282 ◽

Cited By ~ 30

Author(s):

Patrice Lamarre ◽

Denis Lebel ◽

Murray P. Ducharme

Keyword(s):

Pediatric Patients ◽

Pediatric Population ◽

Predictive Ability ◽

Volume Of Distribution ◽

Population Characteristics ◽

Rank Test ◽

Population Pharmacokinetic ◽

Good Precision ◽

Weighted Residuals ◽

Population Pk

ABSTRACT The objectives of this study were to (i) construct a population pharmacokinetic (PK) model able to describe vancomycin (VAN) concentrations in serum in pediatric patients, (ii) determine VAN PK parameters in this population, and (iii) validate the predictive ability of this model in a naive pediatric population. Data used in this study were obtained from 78 pediatric patients (under 18 years old). PK analyses were performed using compartmental methods. The most appropriate model was chosen based on the evaluation of pertinent graphics and calculation of the Akaike information criterion test. The population PK analysis was performed using an iterative two-stage method. A two-compartment PK model using age, sex, weight, and serum creatinine as covariates was determined to be the most appropriate one to describe serum VAN concentrations. The quality of fit was very good, and the distribution of weighted residuals was found to be homoscedastic (Wilcoxon signed rank test). Fitted population PK parameters (mean ± standard deviation) were as follows: central clearance (0.1 ± 0.05 liter/h/kg), central volume of distribution (0.27 ± 0.07 liter/kg), peripheral volume of distribution (0.16 ± 0.07 liter/kg), and distributional clearance (0.16 ± 0.07 liter/kg). The predictive ability of the developed model (including the above-mentioned covariates) was evaluated in a naive population of 19 pediatric patients. The predictability was very good. Precision (±95% confidence interval [CI]) (peak, 4.1 [±1.4], and trough, 2.2 [±0.7]) and bias (±95% CI) (peak, −0.58 [±2.2], and trough, 0.63 [±1.1] mg/liter) were significantly (P < 0.05) superior to those obtained using a conventional method (precision [±95% CI]: peak, 8.03 [±2.46], and trough, 2.7 [±0.74]; bias: peak, −7.1 [±2.9], and trough, −1.35 [±1.2] mg/liter). We propose the use of this population PK model to optimize VAN clinical therapies in our institution and others with similar patient population characteristics.

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Modeling and Simulation Analysis of Aprepitant Pharmacokinetics in Pediatric Patients With Postoperative or Chemotherapy-Induced Nausea and Vomiting

The Journal of Pediatric Pharmacology and Therapeutics ◽

10.5863/1551-6776-25.6.528 ◽

2020 ◽

Vol 25 (6) ◽

pp. 528-539

Author(s):

Anne Chain ◽

Rebecca Wrishko ◽

Grygoriy Vasilinin ◽

Samer Mouksassi

Keyword(s):

Pediatric Patients ◽

Simulation Analysis ◽

Pediatric Population ◽

Plasma Concentrations ◽

Model Development ◽

Postoperative Nausea And Vomiting ◽

Nausea And Vomiting ◽

Fixed Dose ◽

Population Pharmacokinetic ◽

Population Pk

OBJECTIVES Aprepitant is effective for the prevention of chemotherapy-induced or postoperative nausea and vomiting (CINV/PONV). The aim of this study was to develop a population pharmacokinetic (PK) model of aprepitant in pediatric patients and to support dosing recommendations for oral aprepitant in pediatric patients at risk of CINV. METHODS A population PK model was constructed based on data from 3 clinical studies in which children (6 months to 12 years) and adolescents (12–19 years) were treated with a 3-day regimen of oral aprepitant (capsules or suspension), with or without intravenous fosaprepitant on day 1 (CINV), or a single dose of oral aprepitant (capsules or suspension; PONV). Nonlinear mixed-effects modeling was used for model development, and a stepwise covariate search determined factors influencing PK parameters. Simulations were performed to guide final dosing strategies of aprepitant in pediatric patients. RESULTS The analysis included 1326 aprepitant plasma concentrations from 147 patients. Aprepitant PK was described by a 2-compartment model with linear elimination and first-order absorption, with allometric scaling for central and peripheral clearance and volume using body weight, and a cytochrome P450 3A4 maturation component for the effect of ontogeny on systemic clearance. Simulations established that application of a weight-based (for those <12 years) and fixed-dose (for those 12–17 years) dosing regimen results in comparable exposures to those observed in adults. CONCLUSIONS The developed population PK model adequately described aprepitant PK across a broad pediatric population, justifying fixed (adult) dosing for adolescents and weight-based dosing of oral aprepitant for children.

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The first study in pediatric: Population pharmacokinetics of sirolimus and its application in Chinese children with immune cytopenia

International Journal of Immunopathology and Pharmacology ◽

10.1177/2058738420934936 ◽

2020 ◽

Vol 34 ◽

pp. 205873842093493

Author(s):

Xiaoling Cheng ◽

Yiming Zhao ◽

Hao Gu ◽

Libo Zhao ◽

Yannan Zang ◽

...

Keyword(s):

Pediatric Patients ◽

Total Bilirubin ◽

Pediatric Population ◽

Visual Predictive Check ◽

Individual Variability ◽

Chinese Children ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Dose Individualization ◽

Population Pk

The narrow therapeutic index and large inter-individual variability in sirolimus pharmacokinetics (PK) make therapeutic drug monitoring (TDM) necessary. Factors responsible for PK variability are not well understood, and published PK studies do not include pediatric patients with immune cytopenia. The objective of this study was to characterize the PK of sirolimus in pediatric patients with immune cytopenia and to develop a population PK model in Chinese children and evaluate its utility for dose individualization. A total of 27 children with either acquired or congenital immune cytopenia aged 8.16 ± 3.60 years (range: 1–15 years) were included. TDM data for sirolimus were collected. The population PK model of sirolimus was described using the nonlinear mixed-effects modeling (Phoenix NLME 1.3 software) approach. Covariate analysis was applied to select candidate factors associated with PK parameters. The final model was validated using bootstrap (1000 runs) and visual predictive check (VPC) method. A one-compartment model with first-order absorption and elimination was developed. The outcome parameters were as follows: apparent clearance (CL/F) 5.63 L/h, apparent distribution volume (V/F) 144.16 L. Inter-individual variabilities for CL/F and V/F were 3.53% and 7.27%, respectively. The intra-individual variability of proportional error model was 22.45%. The covariate test found that body weight and total bilirubin were strongly associated with clearance; however, we did not find the relevance between the covariate and volume of distribution of sirolimus. Personalized dosage regimens were provided based on Bayesian method. The oral dose should be adjusted according to weight and total bilirubin. This is the first study to describe a population PK model of sirolimusin pediatric patients with immune cytopenia. Population pharmacokinetic (PPK) model–based dose individualization of sirolimus and the design of future clinical studies in children will be facilitated by the developed model in this study.

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Paranasal Mass in a Healthy Male Toddler

Ear Nose & Throat Journal ◽

10.1177/01455613211007944 ◽

2021 ◽

pp. 014556132110079

Author(s):

Melonie Anne Phillips ◽

Meredith Lind ◽

Gerd McGwire ◽

Diana Rodriguez ◽

Suzanna Logan

Keyword(s):

Differential Diagnosis ◽

Pediatric Patients ◽

Pediatric Population ◽

Age Group ◽

Significant Morbidity ◽

Healthy Male ◽

Neck Tumors ◽

Complete Surgical Resection ◽

Maxilla And Mandible ◽

Benign Mass

Head and neck tumors are rare in pediatric patients but should be kept in the differential when a patient presents with a new swelling or mass. One of these tumors is a myxoma, which is an insidiously growing, benign mass originating from the mesenchyme. They most commonly arise in the myocardium but can also develop in facial structures, particularly in the maxilla and mandible. When arising in facial structures, ocular, respiratory, and digestive systems can be affected based on local invasion. Complete surgical resection is curative but can lead to significant morbidity as well. Here, we present a case of a 15-month-old toddler presenting with a paranasal mass, which was ultimately diagnosed as a maxillary myxoma. This tumor is very rare in the pediatric population, especially in the toddler age-group, reminding clinicians to broaden the differential diagnosis when a patient’s course is atypical.

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Endoscopic retrograde cholangiopancreatography in infants and children

Endoscopy International Open ◽

10.1055/a-1337-2212 ◽

2021 ◽

Vol 09 (03) ◽

pp. E292-E296

Author(s):

Tone Lise Åvitsland ◽

Lars Aabakken

Keyword(s):

Endoscopic Retrograde Cholangiopancreatography ◽

Medical Records ◽

Pediatric Patients ◽

Biliary Stricture ◽

Infants And Children ◽

University Hospital ◽

Older Children ◽

Endoscopic Retrograde ◽

Procedure Codes ◽

In Infants And Children

Abstract Background and study aims Previous reports have suggested that endoscopic retrograde cholangiopancreatography (ERCP) in pediatric patients are safe. However, the total number of cases presented in the literature remains small. We present results regarding safety and outcomes in pediatric patients undergoing ERCP at Oslo University Hospital. Patients and methods Patients < 18 years who underwent ERCP between April 1999 and November 2017 were identified using procedure codes. Medical records were examined for age, gender, diagnosis, indications, type of sedation, findings, interventions, and complications. Results A total of 244 procedures were performed in 158 patients. Fifty-six of these were in 53 infants (age ≤ 1 year). Mean age was 8.8 years. The youngest patient was 8 days old. Mean weight was 5.0 kg in infants, the smallest weighing 2.9 kg. Cannulation failed in 19 (7.8 %). The main indication in infants was suspicion of biliary atresia (n = 38). Six of the procedures (10.7 %) were therapeutic. In children the main indications were biliary stricture (n = 64) and investigation of primary sclerosing cholangitis (PSC) (n = 45). 119 (63.2 %) of these procedures were therapeutic.Complications were uncommon in infants; only two episodes of infection were registered. In children (> 1 year) post-ERCP pancreatitis were seen in 10.4 %. Conclusions Our retrospective series of ERCP procedures includes 56 procedures in infants, which is one of the largest series presented. Complications in infants are rare and post-ERCP pancreatitis was not seen. In older children 10.4 % experienced post-ERCP pancreatitis. In expert hands, ERCP was shown to be acceptably feasible and safe in infants and children.

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1346. Implementation of a Multidisciplinary 48 Hour Antibiotic Timeout in a Pediatric Population

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1528 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S684-S684

Author(s):

Victoria Konold ◽

Palak Bhagat ◽

Jennifer Pisano ◽

Natasha N Pettit ◽

Anish Choksi ◽

...

Keyword(s):

Pediatric Patients ◽

Pediatric Population ◽

Intervention Group ◽

Post Intervention ◽

Days Of Therapy ◽

New Antibiotics ◽

Core Elements ◽

Quasi Experimental ◽

Empirical Antibiotics ◽

The Impact

Abstract Background To meet the core elements required for antimicrobial stewardship programs, our institution implemented a pharmacy-led antibiotic timeout (ATO) process in 2017 and a multidisciplinary ATO process in 2019. An antibiotic timeout is a discussion and review of the need for ongoing empirical antibiotics 2-4 days after initiation. This study sought to evaluate both the multidisciplinary ATO and the pharmacy-led ATO in a pediatric population, compare the impact of each intervention on antibiotic days of therapy (DOT) to a pre-intervention group without an ATO, and to then compare the impact of the pharmacy-led ATO versus multidisciplinary ATO on antibiotic days of therapy (DOT). Methods This was a retrospective, pre-post, quasi-experimental study of pediatric patients comparing antibiotic DOT prior to ATO implementation (pre-ATO), during the pharmacy-led ATO (pharm-ATO), and during the multidisciplinary ATO (multi-ATO). The pre-ATO group was a patient sample from February-September 2016, prior to the initiation of a formal ATO. The pharmacy-led ATO was implemented from February-September 2018. This was followed by a multidisciplinary ATO led by pediatric residents and nurses from February-September 2019. Both the pharm-ATO and the multi-ATO were implemented as an active non-interruptive alert added to the electronic health record patient list. This alert triggered when new antibiotics had been administered to the patient for 48 hours, at which time, the responsible clinician would discuss the antibiotic and document their decision via the alert workspace. Pediatric patients receiving IV or PO antibiotics administered for at least 48 hours were included. The primary outcome was DOT. Secondary outcomes included length of stay (LOS) and mortality. Results 1284 unique antibiotic orders (n= 572 patients) were reviewed in the pre-ATO group, 868 (n= 323 patients) in the pharm-ATO and 949 (n= 305 patients) in the multi-ATO groups. Average DOT was not significantly different pre vs post intervention for either methodology (Table 1). Mortality was similar between groups, but LOS was longer for both intervention groups (Table 1). Impact of an ATO on DOT, Mortality and LOS Conclusion An ATO had no impact on average antibiotic DOT in a pediatric population, regardless of the ATO methodology. Disclosures All Authors: No reported disclosures

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Parenteral Histamine2-Receptor Antagonists in the Pediatric Population

Journal of Pharmacy Technology ◽

10.1177/875512259401000203 ◽

1994 ◽

Vol 10 (2) ◽

pp. 53-57

Author(s):

Neeta Bahal O'Mara ◽

Milap C. Nahata

Keyword(s):

Product Information ◽

Pediatric Population ◽

Data Extraction ◽

Infants And Children ◽

Optimal Dosage ◽

Receptor Antagonists ◽

Study Selection ◽

Stability Data ◽

Administration Methods ◽

In Infants And Children

Objective: To provide a review of the use of parenteral histamine2 (H2)-receptor antagonists cimetidine, ranitidine, and famotidine in the pediatric population. Data Sources: Information was identified by MEDLINE and a review of journals. References cited in published articles and manufacturers' product information also were used. Study Selection: Information was selected for review if it addressed the parenteral administration of H2-receptor antagonists in the pediatric population. Data Extraction: Data were extracted from references pertaining to the topic. Data Synthesis: Despite the lack of Food and Drug Administration pediatric labeling, the H2-receptor antagonists often are used for a variety of indications in infants and children. Although these agents differ somewhat in chemical structure, potency, and pharmacokinetics, the most important differences exist in their drug interactions and adverse effect profiles. Further, administration methods, compatibility, and stability data differ slightly among the agents. Conclusions: Parenteral H2-receptor antagonists are used for a variety of indications in infants and children. Despite their widespread use, additional studies are needed to define the optimal dosage regimens in this population.

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The Specific Characteristics in Children with Obstructive Sleep Apnea and Cor Pulmonale

The Scientific World JOURNAL ◽

10.1100/2012/757283 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 9

Author(s):

Pi-Chang Lee ◽

Betau Hwang ◽

Wen-Jue Soong ◽

C. C. Laura Meng

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Pediatric Patients ◽

Pediatric Population ◽

Clinical Manifestations ◽

Cor Pulmonale ◽

Arousal Index ◽

Obstructive Sleep ◽

Hemodynamic Characteristics ◽

Pulmonary Arterial

Background.The prevalence of obstructive sleep apnea (OSA) in the pediatric population is currently estimated at 1-2% of all children. The purpose of this study was to investigate the clinical and hemodynamic characteristics in pediatric patients with cor pulmonale and OSA.Methods.Thirty children with the diagnosis of OSA were included. These patients consisted of 26 male and 4 female children with a mean age of 7 ± 4 years old. Five of those children were found to be associated with cor pulmonale, and 25 had OSA but without cor pulmonale.Results.The arousal index was much higher in children with OSA and cor pulmonale. The children with OSA and cor pulmonale had much lower mean and minimal oxygen saturation and a higher incidence of bradycardia events. All 5 patients with OSA and cor pulmonale underwent an adenotonsillectomy, and the pulmonary arterial pressure dropped significantly after the surgery.Conclusion.This study demonstrated that the OSA pediatric patients with cor pulmonale had the different clinical manifestations and hemodynamic characteristics from those without cor pulmonale. The adenotonsillectomy had excellent results in both the OSA pediatric patients with and without cor pulmonale.

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MR-Proadrenomedullin as biomarker of renal damage in urinary tract infection in children

BMC Pediatrics ◽

10.1186/s12887-021-02765-2 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Rafael Peñalver Penedo ◽

Marta Rupérez Lucas ◽

Luis Antonio Álvarez-Sala Walther ◽

Alicia Torregrosa Benavent ◽

María Luisa Casas Losada ◽

...

Keyword(s):

Urinary Tract Infection ◽

Urinary Tract ◽

Tract Infection ◽

Pediatric Patients ◽

Pediatric Population ◽

Adult Population ◽

Roc Curves ◽

Renal Scintigraphy ◽

Reactive Protein ◽

Sensitivity Specificity

Abstract Background Midregional-proadrenomedullin (MR-proADM) is a useful prognostic peptide in severe infectious pathologies in the adult population. However, there are no studies that analyze its utility in febrile urinary tract infection (fUTI) in children. An accurate biomarker would provide an early detection of patients with kidney damage, avoiding other invasive tests like renal scintigraphy scans. Our objective is to study the usefulness of MR-proADM as a biomarker of acute and chronic renal parenchymal damage in fUTI within the pediatric population. Methods A prospective cohort study was conducted in pediatric patients with fUTI between January 2015 and December 2018. Plasma and urine MR-proADM levels were measured at admission in addition to other laboratory parameters. After confirmation of fUTI, renal scintigraphy scans were performed during the acute and follow-up stages. A descriptive study has been carried out and sensitivity, specificity and ROC curves for MR-proADM, C-reactive protein, and procalcitonin were calculated. Results 62 pediatric patients (34 female) were enrolled. Scintigraphy showed acute pyelonephritis in 35 patients (56.5%). Of those patients, the median of plasmatic MR-proADM (P-MR-proADM) showed no differences compared to patients without pyelonephritis. 7 patients (11.3%) developed renal scars (RS). Their median P-MR-proADM levels were 1.07 nmol/L (IQR 0.66–1.59), while in patients without RS were 0.48 nmol/L (0.43–0.63) (p < 0.01). The AUC in this case was 0.92 (95% CI 0.77–0.99). We established an optimal cut-off point at 0.66 nmol/L with sensitivity 83.3% and specificity 81.8%. Conclusion MR-ProADM has demonstrated a poor ability to diagnose pyelonephritis in pediatric patients with fUTI. However, P-MR-proADM proved to be a very reliable biomarker for RS prediction.

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New Daily Persistent Headache in a Pediatric Population

Journal of Child Neurology ◽

10.1177/08830738211004514 ◽

2021 ◽

pp. 088307382110045

Author(s):

Eric Strong ◽

Emily Linda Pierce ◽

Raquel Langdon ◽

Jeffery Strelzik ◽

William McClintock ◽

...

Keyword(s):

Pediatric Patients ◽

Medication Overuse ◽

Pediatric Population ◽

Medication Overuse Headache ◽

Activity Level ◽

New Daily Persistent Headache ◽

Tertiary Referral Center ◽

Preventive Medication ◽

Headache Clinic ◽

Persistent Headache

Introduction: New daily persistent headache (NDPH) is a primary headache disorder characterized by an intractable, daily, and unremitting headache lasting for at least 3 months. Currently, there are limited studies in the pediatric population describing the characteristics of NDPH. Objective: The objective of the current study is to describe the characteristics of NDPH in pediatric patients presenting to a headache program at a tertiary referral center. Methods: The participants in the current study were pediatric patients who attended the Headache Clinic at Children’s National Hospital between 2016 and 2018. All patients seen in the Headache Clinic were enrolled in an institutional review board–approved patient registry. Results: Between 2016 and 2018, NDPH was diagnosed in 245 patients, representing 14% of the total headache population. NDPH patients were predominantly female (78%) and white (72%). The median age was 14.8 years. The median pain intensity was 6 of 10 (standard deviation = 1.52). Most patients reported experiencing migrainous features, namely, photophobia (85%), phonophobia (85%), and a reduced activity level (88%). Overall, 33% of patients had failed at least 1 preventive medication, and 56% had failed at least 1 abortive medication. Furthermore, 36% of patients were additionally diagnosed with medication overuse headache. Conclusion: NDPH is a relatively frequent disorder among pediatric chronic headache patients. The vast majority of these patients experience migrainous headache characteristics and associated symptoms and are highly refractory to treatment—as evidenced by a strong predisposition to medication overuse headache and high rates of failed preventive management.

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